Raf kinase modulator compounds and methods of use thereof

ABSTRACT

Compounds, compositions and methods are provided for modulating the activity of RAF kinases, including BRAF kinase and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder mediated by RAF kinases.

RELATED APPLICATIONS

This application claims priority to U.S. provisional application Nos.61/069,763, filed Mar. 17, 2008 and 61/110,508 file Oct. 31, 2008. Thedisclosures of the above referenced applications are incorporated byreference herein in their entireties.

FIELD

Provided herein are compounds that are modulators of RAF kinases,including BRAF kinase, compositions comprising the compounds and methodsof use thereof. The compounds provided are useful in the treatment,prevention, or amelioration of a disease or disorder related to RAF,including BRAF kinase, activity or one or more symptoms thereof.

BACKGROUND

Protein kinases (PKs) are enzymes that catalyze the phosphorylation ofhydroxyl groups on tyrosine, serine or threonine residues of proteins.Protein kinases act primarily as growth factor receptors and play acentral role in signal transduction pathways regulating a number ofcellular functions, such as cell cycle, cell growth, celldifferentiation and cell death.

One important signal transduction pathway is the mitogen-activatedprotein kinase (MAPK) pathway. The MAPK signaling pathway is responsiblefor the regulation of cell growth, differentiation, proliferation andsurvival and its dysregulation is implicated in a broad spectrum ofcancer. (Hoshino, et al., Oncogene, 1999, 18, 813-822)

The MAPK signaling pathway is one of multiple signaling pathwaysactivated by GTP-bound RAS. Initially, extracellular stimuli such asmitogens, hormones or neurotransmitters induce receptor tyrosine kinasedimerization leading to increased levels of GTP-bound RAS. Activated RASrecruits dimerized RAF kinase to the plasma membrane whereby RAF isactivated by autophosphorylation or phosphorylation by other kinases.The activation of RAF initiates the phosphorylation cascade down theMEK/ERK pathway, in which activated RAF phosphorylates and activatesMEK1/2 which in turn phosphorylates and activates ERK (or extracellularsignal-regulated kinase, also called p44/42 MAPK) which in turnphosphorylates a number of targets including nuclear transcriptionfactors that lead to changes in gene expression.

RAF is a family of serine/threonine kinases comprising three isoformscalled ARAF, BRAF and CRAF (also called raf-1). BRAF is currently acancer therapeutic target, as mutations in the BRAF gene are among themost common in cancer (Haluska, et al., Clin Cancer Res 2006, 12(7 Pt2), 2301s-2307s; Ikediobi, et al., Mol. Cancer Ther. 2006 5(11),2606-2612; Greenman, et al., Nature 2007 226(7132), 153-158). Themajority of mutant BRAF have been found to exhibit elevated kinaseactivity as measured by levels of phosphorylated MEK or ERK foundendogenously in COS cells (Wan et al. Cell 2004 116, 855-867). BRAFmutations have been identified in about 7% of all known cancers,including 27-70% of melanoma (Davies et al. Nature, 2002 417, 949-954),42-50% of papillary thyroid carcinoma, 36-53% colorectal cancers, and5-22% serous ovarian cancers and to a lesser extent in breast cancer,endometrial cancer, liver cancer, sarcoma, stomach cancer, Barret'sadenocarcinoma, gliomas including ependymomas and lung cancer including1-2% of non small cell lung cancer (See Davies et al. Nature, 2002, 417,949-954; Garnett and Marais, Cancer Cell, 2004 6, 313-319; Ouyang et al.Clin Cancer Res 2006 12(6), 1785-1793; Melillo, et al., J. Clin. Invest.2005, 115, 1068-1081; Wilhelm, et al., Nat. Rev. Drug Discov., 2006 5,835-844; and Ji et al. Cancer Res 2007 67(10), 4933-4939). Over fortydifferent missense mutations of BRAF have been identified, but amongthem, the V600E mutation, has been found to be the most predominant(Fecher, et al., J. Clin. Oncology 2007, 25(12), 1606-1620), accountingfor nearly 90% of the mutations in melanoma and thyroid cancer and for ahigh proportion in colorectal cancer, which makes this mutation aparticularly attractive target for molecular therapy. A study of thecrystal structures of both wild type and V600 mutants suggests thatsubstitution at the 600 position destabilizes the inactive conformationof the enzyme (Wan et al. op cit.). However, V600E mutation iscomparatively rare in non-small cell lung cancer, which is more likelythan not to be associated with non-V600E BRAF missense mutations (Broseet al. Cancer Res., 2002 62, 6997-7000). Other non-V600E BRAF missensemutations are also implicated in melanoma, breast cancer, lung cancer,colorectal cancer, liver cancer, ovarian cancer, leukemia includingacute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma, Barret'sadenocarcinoma, endometrial cancer, liver cancer, stomach cancer,thyroid cancer and endometrial cancer (Garnett and Marais, op. cit.).

In vivo efficacy has been demonstrated for BRAF inhibitors NVP-AAL881-NX(also AAL881) and NVP-L T613-AG-8 (LBT613) in mouse tumor xenograftmodels using human cell lines (See, Ouyang et al. op. cit.). Preclinicalstudies have also shown that BRAF inhibition by siRNA or by the smallmolecule RAF kinase inhibitor Sorafenib resulted in a decrease in tumorgrowth or metastases in animals (Sharma et al. Cancer Res., 2005, 65(6),2412-2421; Sharma et al. Cancer Res., 2006, (66)16, 8200-8209). RAFinhibitors that have entered clinical trials include antisenseoligonucleotides against CRAF such as ISIS 5132 and LErafAON and smallmolecule BRAF inhibitors such as BAY 43-9006 (Sorafenib), Raf-265(formerly CHIR-265, Novartis), PLX-4032 (Plexxikon) and XL281(Exelixis).

Although most BRAF mutations are activating mutations, mutants havingimpaired kinase activity have been identified, and shown to stimulateERK activity, presumably through recruitment of CRAF (Wan op cit.).Therefore, CRAF represents another target for the treatment of diseasesassociated with this particular subset of BRAF mutants.

Outside of cancer, the MAPK (Raf-Mek-Erk) signaling pathway couldprovide targets for inflammation and inflammatory diseases. The MAPKpathway is known to control cell survival and apoptosis of inflammatorycells such as basophils, macrophages, neutrophils and monocytes (SeeDong et al., Annu. Rev. Immunol., 2002, 20, 55-72; Johnson, et al.,Curr. Opin. Chem. Biol., 2005, 9, 325-331; R. Herrera and J. S.Sebolt-Leopold, Trends Mol. Med., 2002, 8, S27-S3; and Kyriakis et al.,Physiol. Rev., 2002, 81, 807-869). In the carrageenan-induced pleurisyrat model, it has been shown that the Erk1/2 inhibitor PD98059 inhibitseosinophilic proinflammtory cytokine release by increasing the rate ofneutrophil apoptosis thereby decreasing the number of macrophage andneutrophils that perpetuate the inflammatory response (Sawatzky et al.,Am J Pathol 2006, 168(1), 33-41). It is therefore possible that onedownstream effect of inhibiting RAF might be the resolution of aninflammatory response and BRAF inhibitors could be useful for thetreatment of inflammatory diseases or immune system disorders includinginflammatory bowel disease, Crohn's disease, ulcerative colitis,systemic lupus erythematosis (SLE), rheumatoid arthritis, multiplesclerosis, thyroiditis, type 1 diabetes, sarcoidosis, psoriasis,allergic rhinitis, asthma, COPD (chronic obstructive pulmonary disease)(See Stanton et al. Dev. Biol. 2003 263,165-175, Hofman et al. Curr.Drug Targets. Inflamm. Allergy 2004 2,1-9).

Given the multitude of diseases attributed to the dysregulation of MAPKsignaling, there is an ever-existing need to provide novel classes ofcompounds that are useful as inhibitors of enzymes in the MAPK signalingpathway, as discussed herein.

SUMMARY

Provided herein are compounds of formula I. In one embodiment, compoundsprovided herein have activity as modulators of RAF kinase, includingBRAF kinase. The compounds are useful in medical treatment,pharmaceutical compositions and methods for modulating the activity ofRAF kinase, including BRAF kinase such as wildtype and/or mutated formsof BRAF kinase. In one embodiment, the compounds have formula (I):

or pharmaceutically acceptable salts, solvates, hydrates or clathratesthereof, wherein

X is O, S(O)_(t);

R^(a) is O or S;

R¹ is selected as follows:

i) each R¹ is independently selected from a group consisting of halo,nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, —R⁶OR⁷, —R⁶SR⁷, —R⁶S(O)_(t)R⁸, —R⁶N(R⁷)₂, —R⁶OR⁹OR⁷,—R⁶OR⁹SR⁷, —R⁶OR⁹S(O)_(t)R⁸, —R⁶OR⁹S(O)_(t)N(R⁷)₂, —R⁶OR⁹N(R⁷)₂,—R⁶SR⁹OR⁷, —R⁶SR⁹SR⁷, —R⁶SR⁹N(R⁷)₂, —R⁶N(R⁷)R⁹N(R⁷)₂, —R⁶N(R⁷)R⁹OR⁷,—R⁶N(R⁷)R⁹SR⁷, —R⁶CN, —R⁶C(O)R⁷, —R⁶C(O)OR⁷, —R⁶C(O)OR⁹OR⁷,—R⁶C(O)N(R⁷)₂, —R⁶C(O)N(R⁷)OR⁷, —R⁶C(NR⁷)N(R⁷)₂, —R⁶C(O)N(R⁷)R⁹N(R⁷)₂,—R⁶C(O)N(R⁷)R⁹OR⁷, —R⁶C(O)N(R⁷)R⁹SR⁷, —R⁶C(O)SR, —R⁶S(O)_(t)OR⁷,—R⁶S(O)_(t)N(R⁷)₂, —R⁶S(O)_(t)N(R⁷)N(R)₂, —R⁶S(O)_(t)N(R⁷)N═C(R)₂,—R⁶S(O)_(t)N(R⁷)C(O)R⁸, —R⁶S(O)_(t)N(R⁷)C(O)N(R⁷)₂,—R⁶S(O)_(t)N(R⁷)C(NR⁷)N(R⁷)₂, —R⁶OC(O)N(R⁷)₂, —R⁶N(R⁷)C(O)R⁸,—R⁶N(R⁷)C(O)OR⁸, —R⁶N(R⁷)C(O)N(R⁷)₂, —R⁶N(R⁷)C(NR⁷)N(R)₂,—R⁶N(R⁷)C(S)N(R⁷)₂, and —R⁶N(R⁷)S(O)_(t)R⁸, or

ii) any two adjacent R¹ groups together form an alkylenedioxy group;

each R⁶ is independently a direct bond, alkylene chain or alkenylenechain;

each R⁷ is independently selected from (i) or (ii) below:

(i) each R⁷ is selected from a group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl, or

(ii) two R⁷ groups together with the N atom to which they are attachedform a heterocyclyl or heteroaryl;

each R⁸ is independently selected from a group consisting of alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl;

each R⁹ is independently an alkylene chain or an alkenylene chain;

R² is hydrogen, halo, alkyl, amino or alkylamino;

R³ is halo or alkyl;

R⁴ and R⁵ are each independently selected as follows:

a) R⁴ and R⁵ are each independently hydrogen or alkyl, or

b) R⁴ and R⁵, together with the N atom to which they are attached, forman oxo-substituted heterocyclyl;

R¹¹ is aryl, heteroaryl or heterocyclyl;

m is an integer from 0 to 4;

n is an integer from 0 to 4;

t is an integer from 0 to 2; and

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹¹ are optionally substitutedwith one or more substituents independently selected from Q¹, wherein Q¹is nitro, halo, azido, cyano, oxo, thioxo, imino, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)SR^(x), —R^(u)S(O)_(t)R^(w),—R^(u)OC(J)R^(x), —R^(u)OC(J)OR^(x), —R^(u)OC(J)N(R^(y))(R^(z)),—R^(u)OC(J)SR^(x), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))C(J)N(R^(y))(R^(z)), —R^(u)N(R^(x))C(J)SR^(x),—R^(u)Si(R^(w))₃, —R^(u)N(R^(x))S(O)_(t)R^(w),—R^(u)N(R^(x))—R^(u)S(O)₂R^(w), —R^(u)N(R^(x))S(O)₂N(R^(y))(R^(z)),—R^(u)S(O)₂N(R^(Y))(R^(z)), —R^(u)P(O)(R^(v))₂, —R^(u)OP(O)(R^(v))₂,—R^(u)C(J)N(R^(x))S(O)₂R^(w), —R^(u)C(J)N(R^(x))N(R^(x))S(O)₂R^(w),R^(u)C(R^(x))═N(OR^(x)) and —R^(u)C(R^(x))═NN(R^(y))(R^(z)),

when Q¹ is alkyl, alkenyl or alkynyl, each Q¹ is optionally substitutedwith halo, cyano, hydroxy or alkoxy,

when Q¹ is cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each Q¹ is optionallysubstituted with halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cyanoalkyl, alkoxy, hydroxyl, oxo or cyano,

each R^(u) is independently alkylene or a direct bond;

each R^(v) is independently alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, hydroxy, —OR^(x) or —N(R^(y))(R^(z));

R^(w) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

each R^(y) and R^(z) is independently selected from (i) or (ii) below:

(i) R^(y) and R^(z) are each independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl, or

(ii) R^(y) and R^(z), together with the nitrogen atom to which they areattached, form a heterocyclyl or heteroaryl; and

J is O, NR^(x) or S.

In one embodiment, the compound provided herein is a pharmaceuticallyacceptable salt of the compound of formula (I). In one embodiment, thecompound provided herein is a solvate of the compound of formula (I). Inone embodiment, the compound provided herein is a hydrate of compound offormula (I).

Also provided are pharmaceutical compositions formulated foradministration by an appropriate route and means containing effectiveconcentrations of one or more of the compounds provided herein, orpharmaceutically acceptable salts, solvates, and hydrates thereof, andoptionally comprising at least one pharmaceutical carrier.

Such pharmaceutical compositions deliver amounts effective for thetreatment, prevention, or amelioration of diseases or disorders that aremodulated or otherwise affected by RAF kinases, including BRAF kinase,or one or more symptoms or causes thereof. Such diseases or disordersinclude without limitation: cancers, including melanoma, papillarythyroid carcinoma, colorectal, ovarian, breast cancer, endometrialcancer, liver cancer, sarcoma, stomach cancer, Barret's adenocarcinoma,glioma (including ependymoma), lung cancer (including non small celllung cancer), head and neck cancer, acute lymphoblastic leukemia andnon-Hodgkin's lymphoma; and inflammatory diseases or immune systemdisorders, including inflammatory bowel disease, Crohn's disease,ulcerative colitis, systemic lupus erythematosis (SLE), rheumatoidarthritis, multiple sclerosis (MS), thyroiditis, type 1 diabetes,sarcoidosis, psoriasis, allergic rhinitis, asthma, and chronicobstructive pulmonary disease (COPD).

Also provided herein are combination therapies using one or morecompounds or compositions provided herein, or pharmaceuticallyacceptable salts, solvates, hydrates or clathrates thereof, incombination with other pharmaceutically active agents for the treatmentof the diseases and disorders described herein.

In one embodiment, such additional pharmaceutical agents include one ormore chemotherapeutic agents, anti-proliferative agents,anti-inflammatory agents, immunomodulatory agents or immunosuppressiveagents.

The compounds or compositions provided herein, or pharmaceuticallyacceptable salts, solvates, hydrates or clathrates thereof, may beadministered simultaneously with, prior to, or after administration ofone or more of the above agents. Pharmaceutical compositions containinga compound provided herein and one or more of the above agents are alsoprovided.

In certain embodiments, provided herein are methods of treating,preventing or ameliorating a disease or disorder that is modulated orotherwise affected by RAF kinases, including BRAF kinase such as wildtype and/or mutant BRAF kinase, or one or more symptoms or causesthereof. In practicing the methods, effective amounts of the compoundsor compositions containing therapeutically effective concentrations ofthe compounds, which are formulated for systemic delivery, includingparenteral, oral, or intravenous delivery, or for local or topicalapplication are administered to an individual exhibiting the symptoms ofthe disease or disorder to be treated. The amounts are effective toameliorate or eliminate one or more symptoms of the disease or disorder.

Further provided is a pharmaceutical pack or kit comprising one or morecontainers filled with one or more of the ingredients of thepharmaceutical compositions. Optionally associated with suchcontainer(s) can be a notice in the form prescribed by a governmentalagency regulating the manufacture, use or sale of pharmaceuticals orbiological products, which notice reflects approval by the agency ofmanufacture, use of sale for human administration. The pack or kit canbe labeled with information regarding mode of administration, sequenceof drug administration (e.g., separately, sequentially or concurrently),or the like.

These and other aspects of the subject matter described herein willbecome evident upon reference to the following detailed description.

DETAILED DESCRIPTION

Provided herein are compounds of formula (I) that have activity as RAFkinase, including BRAF kinase, modulators. Further provided are methodsof treating, preventing or ameliorating diseases that are modulated byRAF kinases, including BRAF kinase, and pharmaceutical compositions anddosage forms useful for such methods. The methods and compositions aredescribed in detail in the sections below.

A. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications are incorporated by reference in their entirety. In theevent that there are a plurality of definitions for a term herein, thosein this section prevail unless stated otherwise.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to ten carbon atoms, and which is attachedto the rest of the molecule by a single bond, e.g., methyl, ethyl,n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), and the like.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing at least onedouble bond, having from two to ten carbon atoms, and which is attachedto the rest of the molecule by a single bond or a double bond, e.g.,ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and thelike.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing at least onetriple bond, having from two to ten carbon atoms, and which is attachedto the rest of the molecule by a single bond or a triple bond, e.g.,ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-3-ynyl and the like.

“Alkylene” and “alkylene chain” refer to a straight or branched divalenthydrocarbon chain consisting solely of carbon and hydrogen, containingno unsaturation and having from one to eight carbon atoms, e.g.,methylene, ethylene, propylene, n-butylene and the like. The alkylenechain may be attached to the rest of the molecule through any twocarbons within the chain.

“Alkenylene” or “alkenylene chain” refers to a straight or branchedchain unsaturated divalent radical consisting solely of carbon andhydrogen atoms, having from two to eight carbon atoms, wherein theunsaturation is present only as double bonds and wherein the double bondcan exist between any two carbon atoms in the chain, e.g., ethenylene,prop-1-enylene, but-2-enylene and the like. The alkenylene chain may beattached to the rest of the molecule through any two carbons within thechain.

“Alkoxy” refers to the radical having the formula —OR wherein R is alkylor haloalkyl. An “optionally substituted alkoxy” refers to the radicalhaving the formula —OR wherein R is an optionally substituted alkyl asdefined herein.

“Alkynylene” or “alkynylene chain” refers to a straight or branchedchain unsaturated divalent radical consisting solely of carbon andhydrogen atoms, having from two to eight carbon atoms, wherein theunsaturation is present only as triple bonds and wherein the triple bondcan exist between any two carbon atoms in the chain, e.g., ethynylene,prop-1-ynylene, but-2-ynylene, pent-1-ynylene, pent-3-ynylene and thelike. The alkynylene chain may be attached to the rest of the moleculethrough any two carbons within the chain.

“Amino” refers to a radical having the formula —NR′R″ wherein R′ and R″are each independently hydrogen, alkyl or haloalkyl. An “optionallysubstituted amino” refers to a radical having the formula NR′R″ whereinone or both of R′ and R″ are optionally substituted alkyl as definedherein.

“Aryl” refers to a radical of carbocylic ring system, includingmonocyclic, bicyclic, tricyclic, tetracyclic C₆-C₁₈ ring systems,wherein at least one of the rings is aromatic. The aryl may be fullyaromatic, examples of which are phenyl, naphthyl, anthracenyl,acenaphthylenyl, azulenyl, fluorenyl, indenyl and pyrenyl. The aryl mayalso contain an aromatic ring in combination with a non-aromatic ring,examples of which are acenaphene, indene, and fluorene.

“Aralkyl” refers to a radical of the formula —R_(a)R_(b) where R_(a) isan alkyl radical as defined above, substituted by R_(b), an arylradical, as defined above, e.g., benzyl. Both the alkyl and arylradicals may be optionally substituted as defined herein.

“Aralkoxy” refers to a radical of the formula —OR_(a)R_(b) where—R_(a)R_(b) is an aralkyl radical as defined above. Both the alkyl andaryl radicals may be optionally substituted as defined herein.

“Cycloalkyl” refers to a stable monovalent monocyclic or bicyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,having from three to ten carbon atoms, and which is saturated andattached to the rest of the molecule by a single bond, e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl, norbornane,norbornene, adamantyl, bicyclo[2.2.2]octane and the like.

“Cycloalkylalkyl” refers to a radical of the formula —R_(a)R_(d) whereR_(a) is an alkyl radical as defined above and R_(d) is a cycloalkylradical as defined above. The alkyl radical and the cylcoalkyl radicalmay be optionally substituted as defined herein.

“Halo”, “halogen” or “halide” refers to F, Cl, Br or I.

“Haloalkyl” refers to an alkyl group, in certain embodiments, C₁₋₄alkylgroup in which one or more of the hydrogen atoms are replaced byhalogen. Such groups include, but are not limited to, chloromethyl,trifluoromethyl 1-chloro-2-fluoroethyl, 2,2-difluoroethyl,2-fluoropropyl, 2-fluoropropan-2-yl, 2,2,2-trifluoroethyl,1,1-difluoroethyl, 1,3-difluoro-2-methylpropyl,(trifluoromethyl)cyclopropyl and 2,2,2-trifluoro-1,1-dimethyl-ethyl.

“Haloalkenyl” refers to an alkenyl group in which one or more of thehydrogen atoms are replaced by halogen. Such groups include, but are notlimited to, 1-chloro-2-fluoroethenyl.

“Heterocyclyl” refers to a stable 3- to 15-membered non-aromatic ringradical which consists of carbon atoms and from one to five heteroatomsselected from a group consisting of nitrogen, oxygen and sulfur. In oneembodiment, the heterocyclic ring system radical may be a monocyclic,bicyclic or tricyclic ring or tetracyclic ring system, which may includefused or bridged ring systems; and the nitrogen or sulfur atoms in theheterocyclic ring system radical may be optionally oxidized; thenitrogen atom may be optionally quaternized; and the heterocyclylradical may be partially or fully saturated. The heterocyclic ringsystem may be attached to the main structure at any heteroatom or carbonatom which results in the creation of a stable compound. Exemplaryheterocylic radicals include, morpholinyl, tetrahydropyranyl,piperidinyl, piperazinyl and pyrrolidinyl.

“Heteroaryl” refers to a monocyclic or multicyclic aromatic ring system,a heterocyclyl radical as defined above which is aromatic, in certainembodiments, of about 5 to about 20 members where one or more, in oneembodiment 1 to 5, of the atoms in the ring system is a heteroatom, thatis, an element other than carbon, including but not limited to,nitrogen, oxygen or sulfur. The heteroaryl group may be optionally fusedto a benzene ring. The heteroaryl radical may be attached to the mainstructure at any heteroatom or carbon atom which results in the creationof a stable compound. Examples of such heteroaryl radicals include, butare not limited to: acridinyl, benzimidazolyl, benzindolyl,benzisoxazinyl, benzo[4,6]imidazo[1,2-a]pyridinyl, benzofuranyl,benzonaphthofuranyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl,benzotriazolyl, benzothiopyranyl, benzoxazinyl, benzoxazolyl,benzothiazolyl, β-carbolinyl, carbazolyl, cinnolinyl, dibenzofuranyl,furanyl, imidazolyl, imidazopyridinyl, imidazothiazolyl, indazolyl,indolizinyl, indolyl, isobenzothienyl, isoindolinyl, isoquinolinyl,isothiazolidinyl, isothiazolyl, naphthyridinyl, octahydroindolyl,octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxazolopyridinyl,oxazolyl, isoxazolyl, oxiranyl, perimidinyl, phenanthridinyl,phenathrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl,phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyridopyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl,quinolinyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl,triazinyl and triazolyl.

In certain embodiments, the heterocyclic or heteroaryl radicals include,but are not limited to: acridinyl, azepinyl, benzimidazolyl,benzindolyl, benzoisoxazolyl, benzisoxazinyl,benzo[4,6]imidazo[1,2-α]pyridinyl, benzodioxanyl, benzodioxolyl,benzofuranonyl, benzofuranyl, benzonaphthofuranyl, benzopyranonyl,benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl,benzothiopyranyl, benzoxazinyl, benzoxazolyl, benzothiazolyl,β-carbolinyl, carbazolyl, chromanyl, chromonyl, cinnolinyl, coumarinyl,decahydroisoquinolinyl, dibenzofuranyl, dihydrobenzisothiazinyl,dihydrobenzisoxazinyl, dihydrofuryl, dihydropyranyl, dioxolanyl,dihydropyrazinyl, dihydropyridinyl, dihydropyrazolyl,dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl,furanonyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl,imidazopyridinyl, imidazothiazolyl, indazolyl, indolinyl, indolizinyl,indolyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,isobenzothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroindolyl,octahydroisoindolyl, oxadiazolyl, oxazolidinonyl, oxazolidinyl,oxazolopyridinyl, oxazolyl, oxiranyl, perimidinyl, phenanthridinyl,phenathrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl,phthalazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pteridinyl,purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl,pyridopyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuryl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, tetrazolyl, thiadiazolopyrimidinyl, thiadiazolyl,thiamorpholinyl, thiazolidinyl, thiazolyl, thienyl, triazinyl, triazolyland 1,3,5-trithianyl.

“Heteroaralkyl” refers to a radical of the formula —R_(a)R_(f) whereR_(a) is an alkyl radical as defined above and R_(f) is a heteroarylradical as defined herein. The alkyl radical and the heteroaryl radicalmay be optionally substituted as defined herein.

“Heterocyclylalkyl” refers to a radical of the formula —R_(a)R_(e)wherein R_(a) is an alkyl radical as defined above and R_(e) is aheterocyclyl radical as defined herein, where the alkyl radical R_(a)may attach at either the carbon atom or the heteroatom of theheterocyclyl radical R_(e). The alkyl radical and the heterocyclylradical may be optionally substituted as defined herein.

“IC₅₀” refers to an amount, concentration or dosage of a particular testcompound that achieves a 50% inhibition of a maximal response, such ascell growth or proliferation measured via any the in vitro or cell basedassay described herein.

Unless stated otherwise specifically described in the specification, itis understood that the substitution can occur on any atom of the alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group.

“Oxo” refers to ═O.

Pharmaceutically acceptable salts include, but are not limited to, aminesalts, such as but not limited to N,N′-dibenzylethylenediamine,chloroprocaine, choline, ammonia, diethanolamine and otherhydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine,N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethyl-benzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc; and other metal salts, such as but not limited to sodiumhydrogen phosphate and disodium phosphate; and also including, but notlimited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates and fumarates.

As used herein and unless otherwise indicated, the term “hydrate” meansa compound provided herein or a salt thereof, that further includes astoichiometric or non-stoichiometeric amount of water bound bynon-covalent intermolecular forces.

As used herein and unless otherwise indicated, the term “solvate” meansa solvate formed from the association of one or more solvent moleculesto a compound provided herein. The term “solvate” includes hydrates(e.g., mono-hydrate, dihydrate, trihydrate, tetrahydrate and the like).

“Sulfide” refers to the radical having the formula —SR wherein R is analkyl or haloalkyl group. An “optionally substituted sulfide” refers tothe radical having the formula —SR wherein R is an optionallysubstituted alkyl as defined herein.

As used herein, “substantially pure” means sufficiently homogeneous toappear free of readily detectable impurities as determined by standardmethods of analysis, such as thin layer chromatography (TLC), gelelectrophoresis, high performance liquid chromatography (HPLC) and massspectrometry (MS), used by those of skill in the art to assess suchpurity, or sufficiently pure such that further purification would notdetectably alter the physical and chemical properties, such as enzymaticand biological activities, of the substance. Methods for purification ofthe compounds to produce substantially chemically pure compounds areknown to those of skill in the art. A substantially chemically purecompound may, however, be a mixture of stereoisomers. In such instances,further purification might increase the specific activity of thecompound.

Unless specifically stated otherwise, where a compound may assumealternative tautomeric, regioisomeric and/or stereoisomeric forms, allalternative isomers are intended to be encompassed within the scope ofthe claimed subject matter. For example, where a compound is describedas having one of two tautomeric forms, it is intended that the bothtautomers be encompassed herein.

Thus, the compounds provided herein may be enantiomerically pure, or bestereoisomeric or diastereomeric mixtures. In the case of amino acidresidues, such residues may be of either the L- or D-form. Theconfiguration for naturally occurring amino acid residues is generallyL. When not specified the residue is the L form. As used herein, theterm “amino acid” refers to α-amino acids which are racemic, or ofeither the D- or L-configuration. The designation “d” preceding an aminoacid designation (e.g., dAla, dSer, dVal, etc.) refers to the D-isomerof the amino acid. The designation “dl” preceding an amino aciddesignation (e.g., dlPip) refers to a mixture of the L- and D-isomers ofthe amino acid. It is to be understood that the chiral centers of thecompounds provided herein may undergo epimerization in vivo. As such,one of skill in the art will recognize that administration of a compoundin its (R) form is equivalent, for compounds that undergo epimerizationin vivo, to administration of the compound in its (S) form.

It is to be understood that the compounds provided herein may containchiral centers. Such chiral centers may be of either the (R) or (S)configuration, or may be a mixture thereof.

Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers maybe prepared using chiral synthons or chiral reagents, or resolved usingconventional techniques, such as reverse phase HPLC.

As used herein, the term “enantiomerically pure” or “pure enantiomer”denotes that the compound comprises more than 75% by weight, more than80% by weight, more than 85% by weight, more than 90% by weight, morethan 91% by weight, more than 92% by weight, more than 93% by weight,more than 94% by weight, more than 95% by weight, more than 96% byweight, more than 97% by weight, more than 98% by weight, more than98.5% by weight, more than 99% by weight, more than 99.2% by weight,more than 99.5% by weight, more than 99.6% by weight, more than 99.7% byweight, more than 99.8% by weight or more than 99.9% by weight, of thedesired enantiomer.

Where the number of any given substituent is not specified (e.g.,haloalkyl), there may be one or more substituents present. For example,“haloalkyl” may include one or more of the same or different halogens.

In the description herein, if there is any discrepancy between achemical name and chemical structure, the structure preferably controls.

As used herein, “isotopic composition” refers to the amount of eachisotope present for a given atom, and “natural isotopic composition”refers to the naturally occurring isotopic composition or abundance fora given atom. Atoms containing their natural isotopic composition mayalso be referred to herein as “non-enriched” atoms. Unless otherwisedesignated, the atoms of the compounds recited herein are meant torepresent any stable isotope of that atom. For example, unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural isotopiccomposition.As used herein, “isotopically enriched” refers to an atom having anisotopic composition other than the natural isotopic composition of thatatom. “Isotopically enriched” may also refer to a compound containing atleast one atom having an isotopic composition other than the naturalisotopic composition of that atom.As used herein, “isotopic enrichment” refers to the percentage ofincorporation of an amount of a specific isotope at a given atom in amolecule in the place of that atom's natural isotopic abundance. Forexample, deuterium enrichment of 1% at a given position means that 1% ofthe molecules in a given sample contain deuterium at the specifiedposition. Because the naturally occurring distribution of deuterium isabout 0.0156%, deuterium enrichment at any position in a compoundsynthesized using non-enriched starting materials is about 0.0156%. Theisotopic enrichment of the compounds provided herein can be determinedusing conventional analytical methods known to one of ordinary skill inthe art, including mass spectrometry and nuclear magnetic resonancespectroscopy.

“Anti-cancer agents” refers to anti-metabolites (e.g., 5-fluoro-uracil,methotrexate, fludarabine), antimicrotubule agents (e.g., vincaalkaloids such as vincristine, vinblastine; taxanes such as paclitaxel,docetaxel), alkylating agents (e.g., cyclophosphamide, melphalan,carmustine, nitrosoureas such as bischloroethylnitrosurea andhydroxyurea), platinum agents (e.g. cisplatin, carboplatin, oxaliplatin,JM-216 or satraplatin, CI-973), anthracyclines (e.g., doxrubicin,daunorubicin), antitumor antibiotics (e.g., mitomycin, idarubicin,adriamycin, daunomycin), topoisomerase inhibitors (e.g., etoposide,camptothecins), anti-angiogenesis agents (e.g. Sutent® and Bevacizumab)or any other cytotoxic agents, (estramustine phosphate, prednimustine),hormones or hormone agonists, antagonists, partial agonists or partialantagonists, kinase inhibitors, and radiation treatment.

“Anti-inflammatory agents” refers to matrix metalloproteinaseinhibitors, inhibitors of pro-inflammatory cytokines (e.g., anti-TNFmolecules, TNF soluble receptors, and IL1) non-steroidalanti-inflammatory drugs (NSAIDs) such as prostaglandin synthaseinhibitors (e.g., choline magnesium salicylate, salicylsalicyclic acid),COX-1 or COX-2 inhibitors), or glucocorticoid receptor agonists such ascorticosteroids, methylprednisone, prednisone, or cortisone.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (see, Biochem. 1972, 11:942-944).

B. Compounds

In one embodiment, the compounds provided are of formula (I) asdescribed above. In one embodiment, the compounds provided are offormula (I) as described above, where X is O. In one embodiment, thecompounds provided are of formula (I) as described above, where X isS(O)_(t) and t is an integer from 0 to 2.

In one embodiment, the compounds have formula (I) or pharmaceuticallyacceptable salts, solvates, hydrates or clathrates thereof, wherein

X is O, S(O)_(t);

R^(a) is O or S;

R¹ is selected as follows:

i) each R¹ is independently selected from a group consisting of halo,nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, —R⁶OR⁷, —R⁶SR⁷, —R⁶S(O)_(t)R⁸, —R⁶N(R⁷)₂, —R⁶OR⁹OR⁷,—R⁶OR⁹SR⁷, —R⁶OR⁹S(O)_(t)R⁸, —R⁶OR⁹S(O)_(t)N(R⁷)₂, —R⁶OR⁹N(R⁷)₂,—R⁶SR⁹OR⁷, —R⁶SR⁹SR⁷, —R⁶SR⁹N(R⁷)₂, —R⁶N(R⁷)R⁹N(R⁷)₂, —R⁶N(R⁷)R⁹OR⁷,—R⁶N(R⁷)R⁹SR⁷, —R⁶CN, —R⁶C(O)R⁷, —R⁶C(O)OR⁷, —R⁶C(O)OR⁹OR⁷,—R⁶C(O)N(R⁷)₂, —R⁶C(O)N(R⁷)OR⁷, —R⁶C(NR⁷)N(R⁷)₂, —R⁶C(O)N(R⁷)R⁹N(R⁷)₂,—R⁶C(O)N(R⁷)R⁹OR⁷, —R⁶C(O)N(R⁷)R⁹SR⁷, —R⁶C(O)SR, —R⁶S(O)_(t)OR⁷,—R⁶S(O)_(t)N(R⁷)₂, —R⁶S(O)_(t)N(R⁷)N(R)₂, —R⁶S(O)_(t)N(R⁷)N═C(R)₂,—R⁶S(O)_(t)N(R⁷)C(O)R⁸, —R⁶S(O)_(t)N(R⁷)C(O)N(R⁷)₂,—R⁶S(O)_(t)N(R⁷)C(NR⁷)N(R⁷)₂, —R⁶OC(O)N(R⁷)₂, —R⁶N(R⁷)C(O)R⁸,—R⁶N(R⁷)C(O)OR⁸, —R⁶N(R⁷)C(O)N(R⁷)₂, —R⁶N(R⁷)C(NR⁷)N(R)₂,—R⁶N(R⁷)C(S)N(R⁷)₂, and —R⁶N(R⁷)S(O)_(t)R⁸, or

ii) any two adjacent R¹ groups together form an alkylenedioxy group;

each R⁶ is independently a direct bond, alkylene chain or alkenylenechain;

each R⁷ is independently selected from (i) or (ii) below:

(i) each R⁷ is selected from a group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl, or

(ii) two R⁷ groups together with the N atom to which they are attachedform a heterocyclyl or heteroaryl;

each R⁸ is independently selected from a group consisting of alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl;

each R⁹ is independently an alkylene chain or an alkenylene chain;

R² is hydrogen, halo, alkyl, amino or alkylamino;

R³ is halo or alkyl;

R⁴ and R⁵ are each independently selected as follows:

a) R⁴ and R⁵ are each independently hydrogen or alkyl, or

b) R⁴ and R⁵, together with the N atom to which they are attached, forman oxo-substituted heterocyclyl;

R¹¹ is aryl, heteroaryl or heterocyclyl;

m is an integer from 0 to 4;

n is an integer from 0 to 4;

t is an integer from 0 to 2; and

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹¹ are optionally substitutedwith one or more substituents independently selected from Q¹, wherein Q¹is nitro, halo, azido, cyano, oxo, thioxo, imino, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)SR^(x), —R^(u)S(O)_(t)R^(w),—R^(u)OC(J)R^(x), —R^(u)OC(J)OR^(x), —R^(u)OC(J)N(R^(y))(R^(z)),—R^(u)OC(J)SR^(x), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))C(J)N(R^(y))(R^(z)), —R^(u)N(R^(x))C(J)SR^(x),—R^(u)Si(R^(w))₃, —R^(u)N(R^(x))S(O)_(t)R^(w),—R^(u)N(R^(x))—R^(u)S(O)₂R^(w), —R^(u)N(R^(x))S(O)₂N(R^(y))(R^(z)),—R^(u)S(O)₂N(R^(y))(R^(z)), —R^(u)P(O)(R^(v))₂, —R^(u)OP(O)(R^(v))₂,—R^(u)C(J)N(R^(x))S(O)₂R^(w), —R^(u)C(J)N(R^(x))N(R^(x))S(O)₂R^(w),R^(u)C(R^(x))═N(OR^(x)) and —R^(u)C(R^(x))═NN(R^(y))(R^(z)),

when Q¹ is alkyl, alkenyl or alkynyl, each Q¹ is optionally substitutedwith halo, cyano, hydroxy or alkoxy,

when Q¹ is cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each Q¹ is optionallysubstituted with halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cyanoalkyl, alkoxy or hydroxyl,

each R^(u) is independently alkylene or a direct bond;

each R^(v) is independently alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, hydroxy, —OR^(x) or —N(R^(y))(R^(z));

R^(w) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

each R^(y) and R^(z) is independently selected from (i) or (ii) below:

(i) R^(y) and R^(z) are each independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl, or

(ii) R^(y) and R^(z), together with the nitrogen atom to which they areattached, form a heterocyclyl or heteroaryl; and

J is O, NR^(x) or S.

In one embodiment, the compounds provided are of formula (II):

or a pharmaceutically acceptable salt, solvate, clathrate or hydratethereof, wherein

X is O, S, S(O) or SO₂;

R¹ is selected as follows:

i) each R¹ is independently selected from the group consisting of, halo,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —R⁶OR⁷,—R⁶SR⁷, —R⁶S(O)_(t)R⁸, —R⁶N(R⁷)₂, —R⁶OR⁹OR⁷, —R⁶OR⁹SR⁷,—R⁶OR⁹S(O)_(t)R⁸, —R⁶OR⁹S(O)_(t)N(R⁷)₂, —R⁶OR⁹N(R⁷)₂, —R⁶SR⁹OR⁷,—R⁶SR⁹SR⁷, —R⁶SR⁹N(R⁷)₂, —R⁶N(R⁷)R⁹N(R⁷)₂, —R⁶N(R⁷)R⁹OR⁷, —R⁶N(R⁷)R⁹SR⁷,—R⁶CN, —R⁶C(O)R⁷, —R⁶C(O)OR⁷, —R⁶C(O)OR⁹OR⁷, —R⁶C(O)N(R⁷)₂,—R⁶C(O)N(R⁷)OR⁷, —R⁶C(O)N(R⁷)R⁹OR⁷, —R⁶C(O)N(R⁷)R⁹SR⁷, —R⁶C(O)SR⁸,—R⁶S(O)_(t)OR⁷, —R⁶OC(O)N(R⁷)₂, —R⁷N(R⁷)C(O)R⁸, —R⁶S(O)_(t)N(R⁷)₂; or

ii) any two adjacent R¹ groups form an alkylenedioxy group;

each R⁶ is independently a direct bond, alkylene chain or alkenylenechain;

each R⁷ is independently selected from (i) or (ii) below:

(i) each R⁷ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl, or

(ii) two R⁷ groups together with the N atom to which they are attachedform a heterocyclyl or heteroaryl;

each R⁹ is independently an alkylene chain or an alkenylene chain;

R² is hydrogen, halo, alkyl, amino or alkylamino;

R³ is halo or alkyl;

R⁴ and R⁵ are each independently hydrogen or alkyl;

R¹¹ is aryl or heteroaryl;

m is an integer from 0 to 4;

n is an integer from 0 to 4;

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹¹ are optionally substitutedwith one or more substituents independently selected from Q¹, wherein Q¹is nitro, halo, azido, cyano, oxo, thioxo, imino, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroaralkyl, —R^(u)OR^(x), —R^(u)OR^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)SR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)OC(J)R^(x),—R^(u)OC(J)OR^(x), —R^(u)OC(J)N(R^(y))(R^(z)), —R^(u)OC(J)SR^(x),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))C(J)N(R^(y))(R^(z)), —R^(u)N(R^(x))C(J)SR^(x),—R^(u)Si(R^(w))₃, —R^(u)N(R^(x))S(O)₂R^(w),—R^(u)N(R^(x))R^(u)S(O)₂R^(w), —R^(u)N(R^(x))S(O)₂N(R^(y))(R^(z)),—R^(u)S(O)₂N(R^(y))(R^(z)), —R^(u)P(O)(R^(v))₂, —R^(u)OP(O)(R^(v))₂,—R^(u)C(J)N(R^(x))S(O)₂R^(w), —R^(u)C(J)N(R^(x))N(R^(x))S(O)₂R^(w),—R^(u)C(R^(x))═N(OR^(x)) and —R^(u)C(R^(x))═NN(R^(y))(R^(z)),

when Q¹ is alkyl, alkenyl or alkynyl, each Q¹ is optionally substitutedwith halo, cyano, hydroxy or alkoxy,

when Q¹ is cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each Q¹ is optionallysubstituted with halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cyanoalkyl, alkoxy or hydroxyl,

each R^(u) is independently alkylene or a direct bond;

each R^(v) is independently alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, hydroxy, —OR^(x) or —N(R^(y))(R^(z));

R^(w) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z), together with the nitrogen atom to which they areattached, form a heterocycle or heteroaryl;

t is an integer from 0 to 2; and

J is O, NR^(x) or S.

In one embodiment, the compounds provided are of formula (II) or apharmaceutically acceptable salt, solvate, clathrate or hydrate thereof,wherein

X is O, S, S(O) or SO₂;

R¹ is selected as follows:

i) each R¹ is independently selected from the group consisting of, halo,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —R⁶OR⁷,—R⁶SR⁷, —R⁶S(O)_(t)R⁸, —R⁶N(R⁷)₂, —R⁶OR⁹OR⁷, —R⁶OR⁹SR⁷,—R⁶OR⁹S(O)_(t)R⁸, —R⁶OR⁹S(O)_(t)N(R⁷)₂, —R⁶OR⁹N(R⁷)₂, —R⁶SR⁹OR⁷,—R⁶SR⁹SR⁷, —R⁶SR⁹N(R⁷)₂, —R⁶N(R⁷)R⁹N(R⁷)₂, —R⁶N(R⁷)R⁹OR⁷, —R⁶N(R⁷)R⁹SR⁷,—R⁶CN, —R⁶C(O)R⁷, —R⁶C(O)OR⁷, —R⁶C(O)OR⁹OR⁷, —R⁶C(O)N(R⁷)₂,—R⁶C(O)N(R⁷)OR⁷, —R⁶C(O)N(R⁷)R⁹OR⁷, —R⁶C(O)N(R⁷)R⁹SR⁷, —R⁶C(O)SR⁸,—R⁶S(O)_(t)OR⁷, —R⁶OC(O)N(R⁷)₂, —R⁶N(R⁷)C(O)R⁸, —R⁶S(O)_(t)N(R⁷)₂; or

ii) any two adjacent R¹ groups form an alkylenedioxy group;

each R⁶ is independently a direct bond, alkylene chain or alkenylenechain;

each R⁷ is independently selected from (i) or (ii) below:

(i) each R⁷ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl, or

(ii) two R⁷ groups together with the N atom to which they are attachedform a heterocyclyl or heteroaryl;

each R⁹ is independently an alkylene chain or an alkenylene chain;

R² is hydrogen, halo, alkyl, amino or alkylamino;

R³ is halo or alkyl;

R⁴ and R⁵ are each independently hydrogen or alkyl;

R¹¹ is aryl or heteroaryl;

m is an integer from 0 to 4;

n is an integer from 0 to 4;

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹¹ are optionally substitutedwith one or more substituents independently selected from Q¹, wherein Q¹is nitro, halo, azido, cyano, oxo, thioxo, imino, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroaralkyl, —R^(u)OR^(x), —R^(u)OR^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)SR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)OC(J)R^(x),—R^(u)OC(J)OR^(x), —R^(u)OC(J)N(R^(y))(R^(z)), —R^(u)OC(J)SR^(x),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))C(J)N(R^(y))(R^(z)), —R^(u)N(R^(x))C(J)SR^(x),—R^(u)Si(R^(w))₃, —R^(u)N(R^(x))S(O)₂R^(w),—R^(u)N(R^(x))R^(u)S(O)₂R^(w), —R^(u)N(R^(x))S(O)₂N(R^(y))(R^(z)),—R^(u)S(O)₂N(R^(y))(R^(z)), —R^(u)P(O)(R^(v))₂, —R^(u)OP(O)(R^(y))₂,—R^(u)C(J)N(R^(x))S(O)₂R^(w), —R^(u)C(J)N(R^(x))N(R^(x))S(O)₂R^(w),—R^(u)C(R^(x))═N(OR^(x)) and —R^(u)C(R^(x))═NN(R^(y))(R^(z)),

when Q¹ is alkyl, alkenyl or alkynyl, each Q¹ is optionally substitutedwith halo, cyano, hydroxy or alkoxy,

when Q¹ is cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each Q¹ is optionallysubstituted with halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cyanoalkyl, oxo, cyano, thioxo, alkoxy or hydroxyl,

each R^(u) is independently alkylene or a direct bond;

each R^(v) is independently alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, hydroxy, —OR^(x) or —N(R^(y))(R^(z));

R^(w) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z), together with the nitrogen atom to which they areattached, form a heterocycle or heteroaryl;

t is an integer from 0 to 2; and

J is O, NR^(x) or S.

In one embodiment, the compound is a single isomer, including astereoisomer, a mixture of isomers, a racemic mixture of isomers, asolvate, a hydrate or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound provided herein is a pharmaceuticallyacceptable salt of the compound of formula (I). In one embodiment, thecompounds provided herein is a solvate of the compound of formula (I).In one embodiment, the compounds provided herein is a hydrate ofcompound of formula (I).

In one embodiment, X is O or S. In one embodiment, X is O. In oneembodiment, X is S(O)_(t) and t is an integer from 0 to 2. In oneembodiment X is S. In one embodiment, R^(a) is O.

In one embodiment, n is an integer from 1 to 4. In one embodiment, nis 1. In one embodiment, n is 2. In one embodiment, n is 3.

In one embodiment, m is an integer from 0 to 2. In one embodiment, m is0. In one embodiment, m is 1. In one embodiment, m is 2.

In one embodiment, R² is hydrogen.

In one embodiment, R³ is lower alkyl or halo. In one embodiment, R³ ismethyl, chloro or fluoro. In another embodiment, R³ is methyl, chloro orfluoro.

In one embodiment, R⁴ is hydrogen or alkyl and R⁵ is hydrogen. In oneembodiment, R⁵ is hydrogen or alkyl and R⁴ is hydrogen. In oneembodiment, R⁴ and R⁵ are each independently hydrogen or methyl. In oneembodiment, R⁴ and R⁵ are each hydrogen.

In one embodiment, Q¹ is nitro, halo, azido, cyano, oxo, thioxo, imino,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl,—R^(u)OR^(x), —R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(Y))(R^(z)), —R^(u)C(J)SR^(x), —R^(u)S(O)_(t)R^(w),—R^(u)OC(J)R^(x), —R^(u)OC(J)OR^(x), —R^(u)OC(J)N(R^(Y))(R^(z)),—R^(u)OC(J)SR^(x), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))C(J)N(R^(Y))(R^(z)), —R^(u)N(R^(x))C(J)SR^(x),—R^(u)Si(R^(w))₃, —R^(u)N(R^(x))S(O)₂R^(w),—R^(u)N(R^(x))R^(u)S(O)₂R^(w), —R^(u)N(R^(x))S(O)₂N(R^(Y))(R^(z)),—R^(u)S(O)₂N(R^(Y))(R^(z)), —R^(u)P(O)(R^(v))₂, —R^(u)OP(O)(R^(v))₂,—R^(u)C(J)N(R^(x))S(O)₂R^(w), —R^(u)C(J)N(R^(x))N(R^(x))S(O)₂R^(w),—R^(u)C(R^(x))═N(OR^(x)) and —R^(u)C(R^(x))═NN(R^(y))(R^(z)),

when Q¹ is alkyl, alkenyl or alkynyl, each Q¹ is optionally substitutedwith halo, cyano, hydroxy or alkoxy,

when Q¹ is cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each Q¹ is optionallysubstituted with halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cyanoalkyl, alkoxy or hydroxyl, wherein the variables are as describedelsewhere herein.

In one embodiment, Q¹ is nitro, halo, azido, cyano, oxo, thioxo, imino,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl,—R^(u)OR^(x), —R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(Y))(R^(z)), —R^(u)C(J)SR^(x), —R^(u)S(O)_(t)R^(w),—R^(u)OC(J)R^(x), —R^(u)OC(J)OR^(x), —R^(u)OC(J)N(R^(Y))(R^(z)),—R^(u)OC(J)SR^(x), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))C(J)N(R^(Y))(R^(z)), —R^(u)N(R^(x))C(J)SR^(x),—R^(u)Si(R^(w))₃, —R^(u)N(R^(x))S(O)₂R^(w),—R^(u)N(R^(x))R^(u)S(O)₂R^(w), —R^(u)N(R^(x))S(O)₂N(R^(Y))(R^(z)),—R^(u)S(O)₂N(R^(Y))(R^(z)), —R^(u)P(O)(R^(v))₂, —R^(u)OP(O)(R^(v))₂,—R^(u)C(J)N(R^(x))S(O)₂R^(w), —R^(u)C(J)N(R^(x))N(R^(x))S(O)₂R^(w),—R^(u)C(R^(x))═N(OR^(x)) and —R^(u)C(R^(x))═NN(R^(y))(R^(z)),

when Q¹ is alkyl, alkenyl or alkynyl, each Q¹ is optionally substitutedwith halo, cyano, hydroxy or alkoxy,

when Q¹ is cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each Q¹ is optionallysubstituted with halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cyanoalkyl, oxo, thioxo, alkoxy or hydroxyl, wherein the variables areas described elsewhere herein.

In one embodiment, Q¹ is halo, alkyl, —R^(u)OR^(x), —R^(u)OR^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)C(J)OR^(x),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))S(O)₂R^(w) or —R^(u)N(R^(x))R^(u)S(O)₂R^(w), when Q¹ is alkyl, each Q¹ is optionally substitutedwith halo, cyano, hydroxy or alkoxy, wherein the variables are asdescribed elsewhere herein.

In one embodiment, Q¹ is halo, alkyl, cycloalkyl, haloalkyl,—R^(u)OR^(x), —R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)),—R^(u)N(R^(y))(R^(z)), —R^(u)C(J)OR^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))S(O)₂R^(w) or —R^(u)N(R^(x)) R^(u)S(O)₂R^(w),

when Q¹ is alkyl, each Q¹ is optionally substituted with halo, cyano,hydroxy or alkoxy,

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(x) is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

R^(y) and R^(z) are each independently hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,heteroaryl, or heteroaralkyl; or

R^(y) and R^(z), together with the nitrogen atom to which they areattached, form a heterocyclyl or heteroaryl.

In one embodiment, Q¹ is halo, alkyl, cycloalkyl, haloalkyl,—R^(u)OR^(x), —R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)),—R^(u)N(R^(y))(R^(z)), —R^(u)C(J)OR^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))S(O)₂R^(w) or —R^(u)N(R^(x)) R^(u)S(O)₂R^(w),

where Q¹, when alkyl is optionally substituted with halo, cyano, andwhere Q¹, when cycloalkyl is optionally substituted with haloalkyl andthe other variables are as described elsewhere herein.

In one embodiment, Q¹ is haloalkyl, alkyl, —R^(u)OR^(x),—R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z))—R^(u)C(J)OR^(x),—R^(u)S(O)₂R^(w), —R^(u)N(R^(x))S(O)₂R^(w) or —R^(u)N(R^(x))R^(u)S(O)₂R^(w), wherein R^(u) is direct bond or alkylene, R^(x) ishydrogen or alkyl; WI is alkyl and J is O, S or NR^(x).

In one embodiment, Q¹ is halo, hydroxy, alkyl, hydroxyalkyl,alkyloxycarbonyl, alkylsulfonyl or haloalkyl.

In one embodiment, the compounds provided herein have formula III:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein m is an integer from 0 to 4 and wherein the other variables areas described elsewhere herein.

In one embodiment, the compounds provided herein have formula IV:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein m is an integer from 0 to 4 and wherein the other variables areas described elsewhere herein.

In one embodiment, R¹¹ is optionally substituted aryl, optionallysubstituted heterocyclyl or optionally substituted heteroaryl, whereinthe substituents, when present are selected from one or more R¹⁰ groups,wherein each R¹⁰ is independently selected from halo, alkyl, alkoxy,haloalkoxy, cycloalkyl, alkoxyalkoxy, aryl, heterocyclyl,heterocyclylcarbonyl, alkoxycarbonyl and heteroaryl, where the alkylgroup is optionally substituted with 1, 2 or 3 groups selected fromhalo, cyano, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl,alkylcarbonyl and alkoxycarbonyl.

In one embodiment, R¹¹ is optionally substituted aryl, optionallysubstituted heterocyclyl or optionally substituted heteroaryl, whereinthe substituents, when present are selected from one or more R¹⁰ groups,wherein each R¹⁰ is independently selected from halo, alkyl, alkoxy,haloalkoxy, cycloalkyl, alkoxyalkoxy, aryl, heterocyclyl,heterocyclylcarbonyl, alkoxycarbonyl and heteroaryl, where the alkylgroup is optionally substituted with 1, 2 or 3 groups selected fromhalo, cyano, haloalkyl, hydroxy, alkoxy, cycloalkyl, aryl, heterocyclyl,alkylcarbonyl and alkoxycarbonyl.

In another embodiment, R¹¹ is optionally substituted aryl, optionallysubstituted heterocyclyl or optionally substituted heteroaryl, whereinthe substituents, when present, are selected from one or more R¹⁰groups, wherein each R¹⁰ is independently selected from halo, alkyl,haloalkyl, alkoxy, haloalkoxy, cycloalkyl, alkoxyalkoxy, aryl, aralkyl,heterocyclyl, heterocyclylcarbonyl, alkoxycarbonyl, heteroaryl andheteroaralkyl where the alkyl group is optionally substituted with 1, 2or 3 groups selected from halo, cyano, haloalkyl, hydroxy, alkoxy,cycloalkyl, heterocyclyl, alkylcarbonyl and alkoxycarbonyl and where thecycloalkyl, aryl and heteroaryl group is optionally substituted with 1,2 or 3 groups selected from halo, cyano, alkyl, haloalkyl, hydroxy andalkoxy. In another embodiment, R¹¹ is optionally substituted aryl,optionally substituted heterocyclyl or optionally substitutedheteroaryl, wherein the substituents, when present, are selected fromone or more R¹⁰ groups, wherein each R¹⁰ is independently selected fromhalo, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heteroaryl and heteroaralkyl where the alkyl group is optionallysubstituted with 1, 2 or 3 groups selected from halo, cyano, haloalkyl,and cycloalkyl, and where the cycloalkyl, aryl and heteroaryl group isoptionally substituted with 1, 2 or 3 groups selected from Q¹. Inanother embodiment, R¹¹ is optionally substituted aryl, optionallysubstituted heterocyclyl or optionally substituted heteroaryl, whereinthe substituents, when present, are selected from one or more R¹⁰groups, wherein each R¹⁰ is independently selected from halo, alkyl,haloalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl andheteroaralkyl where the alkyl group is optionally substituted with 1, 2or 3 groups selected from halo, cyano, haloalkyl, and cycloalkyl, andwhere the cycloalkyl, aryl and heteroaryl groups are optionallysubstituted with 1, 2 or 3 groups selected halo, cyano, alkyl andhaloalkyl.

In one embodiment, R¹¹ is 5-12 membered optionally substitutedheteroaryl having one or more heteroatoms, wherein the heteroatoms areeach independently selected from nitrogen, sulfur and oxygen. In oneembodiment, R¹¹ is 5-6 membered optionally substituted heteroaryl. Inone embodiment, R¹¹ is 5-membered optionally substituted heteroaryl. Inone embodiment, R¹¹ is pyrazole optionally substituted with one, two orthree substitutents, each independently selected from R¹⁰. In anotherembodiment, R¹¹ is isoxazole optionally substituted with one, two orthree substituents, each independently selected from R¹⁰.

In one embodiment, R¹⁰ is independently selected from halo, haloalkyl,alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl where the alkylgroup is optionally substituted with 1 or 2 groups selected from halo,cyano, and cycloalkyl and where the cycloalkyl, aryl and heteroaryl isoptionally substituted with 1 or 2 groups selected from Q¹. In anotherembodiment, R¹⁰ is independently selected from halo, haloalkyl, alkyl,cycloalkyl, aryl, heterocyclyl, and heteroaryl where the alkyl group isoptionally substituted with 1 or 2 groups selected from halo, cyano, andcycloalkyl and where the cycloalkyl, aryl and heteroaryl is optionallysubstituted with 1 or 2 groups selected from halo, cyano, alkyl andhaloalkyl.

In one embodiment, R¹⁰ is independently selected from halo, alkyl,haloalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heterocyclylcarbonyl, alkoxycarbonyl, heteroaryl and heteroaralkyl wherethe alkyl group is optionally substituted with 1, 2 or 3 groups selectedfrom halo, cyano, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl,alkylcarbonyl and alkoxycarbonyl.

In one embodiment, R¹⁰ is independently selected from halo, haloalkyl,alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl where thealkyl group is optionally substituted with 1 or 2 groups selected fromhalo, cyano, and cycloalkyl and where the cycloalkyl, aryl andheteroaryl is optionally substituted with 1 or 2 groups selected fromQ¹. In another embodiment, R¹⁰ is independently selected from halo,haloalkyl, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl andheteroaralkyl where the alkyl group is optionally substituted with 1 or2 groups selected from halo, cyano, and cycloalkyl and where thecycloalkyl, aryl and heteroaryl is optionally substituted with 1 or 2groups selected from halo, cyano, alkyl and haloalkyl.

In one embodiment, each R¹⁰ is independently selected from hydrogen,halo, alkyl, haloalkyl, cyanoalkyl, haloalkoxy, hydroxyalkyl,cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, aryl,heterocyclyl, heterocyclylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkylcarbonylalkyl, heterocyclylalkyl and heteroaryl.

In one embodiment, one R¹⁰ is alkyl or haloalkyl and the other R¹⁰ iscycloalkyl, aryl or heteroaryl optionally substituted with 1, 2 or 3groups selected from Q¹.

In one embodiment, R¹⁰ is alkyl or haloalkyl.

In another embodiment, R¹¹ is optionally substituted aryl, optionallysubstituted heterocyclyl or optionally substituted heteroaryl, whereinthe substituents, when present are selected from F, Cl, methyl, ethyl,n-propyl, —C(CH₃)₃, —CH(CH₃)₂, —C(CH₃)₂CN, —C(CH₃)₂CF₃, —CF(CH₃)₂,—CF₂(CH₃), —C(CH₃)(CH₂F)₂, —CF₃, phenyl, pyridinyl, cyclopropyl,cyclopentyl, cyclohexyl and

where q is an integer from 1-5 and where the phenyl, pyridinyl,cyclopropyl, cyclopentyl or cyclohexyl may be optionally substitutedwith 1 or 2 groups selected from halo, cyano, alkyl, haloalkyl andcyanoalkyl.

In another embodiment, R¹¹ is selected from a group consisting of:

and each R¹⁰ is independently selected from hydrogen, halo, haloalkyl,alkyl, alkoxy, haloalkoxy, cycloalkyl, alkoxyalkoxy, aryl, heterocyclyl,heterocyclylcarbonyl, alkoxycarbonyl and heteroaryl, where the alkylgroup is optionally substituted with, in one embodiment, 1 to 5, inanother embodiment, 1 or 2 groups selected from halo, cyano, hydroxy,alkoxy, cycloalkyl, heterocyclyl, alkylcarbonyl and alkoxycarbonyl. Inone embodiment, alkyl, cycloalkyl, heterocyclyl and heteroaryl groups inR¹⁰ are each independently optionally substituted with 1, 2 or 3 groupsselected from halo, cyano, hydroxyl and alkoxy. In one embodiment, R¹⁰is C₃₋₅ alkyl optionally substituted with 1, 2 or 3 groups selected fromhalo, cyano, hydroxyl and alkoxy. In one embodiment, R¹⁰ is C₄ alkyloptionally substituted with 1, 2 or 3 groups selected from halo, cyano,hydroxyl and alkoxy.

In one embodiment, R¹¹ is

where R¹⁰ is as described elsewhere herein. In one embodiment, R¹⁰ ishydrogen, alkyl, hydroxyalkyl, cycloalkyl, haloalkyl, cyanoalkyl,alkoxyalkyl, aryl or heteroaryl. In one embodiment, R¹⁰ is alkyl. In oneembodiment, one R¹⁰ is alkyl and the other R¹⁰ is hydrogen. In oneembodiment, one R¹⁰ is haloalkyl and the other R¹⁰ is hydrogen. In oneembodiment, one R¹⁰ is alkyl and the other R¹⁰ is aryl. In oneembodiment, R¹⁰ is other than methyl. In one embodiment, R¹⁰ is t-butyl.

In one embodiment, R¹¹ is

where R¹⁰ is as described elsewhere herein. In one embodiment, R¹⁰ ishydrogen, alkyl, hydroxyalkyl, cycloalkyl, haloalkyl, cyanoalkyl,alkoxyalkyl or aryl. In one embodiment, R¹⁰ is —C(CH₃)₃, —CH(CH₃)₂,—C(CH₃)₂CN, —C(CH₃)₂CF₃, —CF(CH₃)₂, —CF₂(CH₃), —C(CH₃)₂CH₂OH,—C(CH₃)(CH₂F)₂, —C(CH₃)₂CH₂OCH₃, CF₃, phenyl, cyclopentyl or

where q is an integer from 1-5.

In one embodiment, R¹¹ is

where R¹⁰ is as described elsewhere herein. In one embodiment, R¹⁰ ishydrogen, alkyl, hydroxyalkyl, cycloalkyl, haloalkyl, cyanoalkyl,alkoxyalkyl or aryl. In one embodiment, R¹⁰ is C(CH₃)₃, —CH(CH₃)₂,—C(CH₃)₂CN, —C(CH₃)₂CF₃, —CF(CH₃)₂, —CF₂(CH₃), —C(CH₃)₂CH₂OH,—C(CH₃)(CH₂F)₂, —C(CH₃)₂CH₂OCH₃, CF₃, phenyl, cyclopentyl or

where q is an integer from 1-5.

In one embodiment, R¹¹ is

In one embodiment, R¹¹ is

In one embodiment, R¹¹ is

In one embodiment, R¹¹ is

In one embodiment, R¹¹ is

In one embodiment, R¹¹ is

In one embodiment, R¹¹ is

In one embodiment, R¹¹ is

In one embodiment, R¹¹ is

In one embodiment, the compounds provided herein have formula VA or VB:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein r is 0, 1 or 2 and the other variables are as describedelsewhere herein. In one embodiment, R¹⁰ is independently selected fromhalo, haloalkyl, alkyl, alkoxy, haloalkoxy, cycloalkyl, alkoxyalkoxy,aryl, heterocyclyl, heterocyclylcarbonyl, alkoxycarbonyl and heteroaryl,where the alkyl group is optionally substituted with 1 or 2 groupsselected from halo, cyano, hydroxy, alkoxy, cycloalkyl, heterocyclyl,alkylcarbonyl and alkoxycarbonyl.

In one embodiment, the compounds provided herein have formula:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein r is 0, 1 or 2 and the other variables are as describedelsewhere herein. In one embodiment, R¹⁰ is independently selected fromhalo, haloalkyl, alkyl, alkoxy, haloalkoxy, cycloalkyl, alkoxyalkoxy,aryl, heterocyclyl, heterocyclylcarbonyl, alkoxycarbonyl and heteroaryl,where the alkyl group is optionally substituted with 1 or 2 groupsselected from halo, cyano, hydroxy, alkoxy, cycloalkyl, heterocyclyl,alkylcarbonyl and alkoxycarbonyl.

In one embodiment, the compounds provided herein have formula:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein r is 0, 1 or 2 and the other variables are as describedelsewhere herein. In one embodiment, R¹⁰ is independently selected fromhalo, haloalkyl, alkyl, alkoxy, haloalkoxy, cycloalkyl, alkoxyalkoxy,aryl, heterocyclyl, heterocyclylcarbonyl, alkoxycarbonyl and heteroaryl,where the alkyl group is optionally substituted with 1 or 2 groupsselected from halo, cyano, hydroxy, alkoxy, cycloalkyl, heterocyclyl,alkylcarbonyl and alkoxycarbonyl.

In one embodiment, the compounds provided herein have formula VI:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein the variables are as described elsewhere herein.

In one embodiment, the compounds provided herein have formula VIa:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein the variables are as described elsewhere herein.

In one embodiment, the compounds provided herein have formula VIb:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein the variables are as described elsewhere herein.

In one embodiment, the compounds provided herein have formula VIc:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein the variables are as described elsewhere herein.

In one embodiment, the compounds provided herein have formula VId:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein the variables are as described elsewhere herein.

In one embodiment, the compounds provided herein have formula VIe:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein the variables are as described elsewhere herein.

In one embodiment, the compounds provided herein have formula VIf:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein the variables are as described elsewhere herein.

In one embodiment, the compounds provided herein have formula VIg:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein the variables are as described elsewhere herein.

In one embodiment, the compounds provided herein have formula VIIa:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein the variables are as described elsewhere herein.

In one embodiment, the compounds provided herein have formula VIIb:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein the variables are as described elsewhere herein.

In one embodiment, R¹¹ is

where each R¹⁰ is independently selected from halo, alkyl, haloalkyl,hydroxyalkyl, cyanoalkyl, alkoxyalkyl, aryl, haloaryl, alkylaryl,heteroaryl and alkoxycarbonylalkyl, and r is 1 or 2. In one embodiment,r is 1, and the R¹⁰ on the N atom of the pyrazole is phenyl optionallysubstituted with halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cyanoalkyl, alkoxy or hydroxy and the other R¹⁰ is selected fromhydrogen, halo, alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl andalkoxyalkyl. In one embodiment, r is 1 and the R¹⁰ on the N atom of thepyrazole is 5 or 6-membered heteroaryl and the other R¹⁰ is selectedfrom hydrogen, halo, alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl andalkoxyalkyl. In one embodiment, r is 1 and the R¹⁰ on the N atom of thepyrazole is selected from pyridinyl, pyrimidinyl, pyrazinyl, quinolyl,isoquinolinyl, quinazolinyl, thiazolyl, thiadiazolyl, imidazolyl,thienyl and furanyl and the other R¹⁰ is selected from hydrogen, halo,alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl and alkoxyalkyl. In oneembodiment, each R¹⁰ is independently selected from hydrogen,tert-butyl, methyl, isopropyl or phenyl; and r is 1.

In one embodiment, R¹¹ is

where R¹⁰ is as defined elsewhere herein. In one embodiment, R¹⁰ on theN atom of the pyrazole is phenyl optionally substituted with halo,alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkoxy orhydroxy and the other R¹⁰ on the carbon atom of the pyrazole is selectedfrom hydrogen, halo, alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl,alkoxyalkyl. In one embodiment, R¹⁰ on the N atom of the pyrazole isheteroaryl optionally substituted with halo, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkoxy or hydroxy and the otherR¹⁰ on the carbon atom of the pyrazole is selected from hydrogen, halo,alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl.

In one embodiment, each R¹⁰ of the pyrazole is independently selectedfrom halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl,cycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl and heteroaralkylwherein each cycloalkyl, aryl, aralkyl, heteroaryl and heteroaralkyl isoptionally substituted with halo, cyano, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl and alkoxyalkyl. In another embodiment, R¹⁰ onthe N atom of the pyrazole is independently selected from halo, alkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, cycloalkyl,heterocyclyl, aryl, aralkyl, heteroaryl and heteroaralkyl wherein eachcycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is optionallysubstituted with halo, cyano, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl and alkoxyalkyl and R¹⁰ on the C atom of thepyrazole is independently selected from halo, alkyl, haloalkyl,cyanoalkyl and cycloalkyl.

In one embodiment, R¹¹ is

where R¹⁰ is hydrogen, halo, alkyl, haloalkyl, hydroxyalkyl, cyanoalkylor alkoxyalkyl; and R^(10a) is hydrogen, halo or alkyl.

In one embodiment, R¹¹ is

where R¹⁰ is as defined elsewhere herein.

In one embodiment, R¹¹ is

where R¹⁰ is hydrogen, halo, alkyl, haloalkyl, hydroxyalkyl, cyanoalkylor alkoxyalkyl.

In one embodiment, R¹¹ is

In one embodiment, R¹¹ is

where R^(10a) is hydrogen, halo, haloalkyl, cyano, alkyl, alkoxy,aminoalkoxy, haloalkoxy or alkylsulfonyl.

In one embodiment, the compounds provided herein have formula VIIIA orVIIIB:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein the variables are as described elsewhere herein.

In one embodiment, the compounds provided herein have formula VIIIC orVIIID:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein the variables are as described elsewhere herein.

In one embodiment, R¹¹ is

where each R¹⁰ is independently selected from halo, alkyl, haloalkyl,hydroxyalkyl, haloalkoxy, cycloalkyl, alkoxyalkyl, alkoxyalkoxy, aryl,heterocyclylalkyl and heterocyclylcarbonyl; and r is an integer from 0to 3. In one embodiment, r is 1, 2 or 3. In one embodiment, r is 1 or 2.In one embodiment, r is 1. In one embodiment, r is 0.

In one embodiment, R¹¹ is

where each R¹⁰ is absent or is independently selected from halo, alkyl,haloalkyl, hydroxyalkyl, haloalkoxy, cycloalkyl, alkoxyalkyl,alkoxyalkoxy, aryl, heterocyclylalkyl and heterocyclylcarbonyl. In oneembodiment, at least one R¹⁰ is absent and the other two R¹⁰ are eachindependently selected from —F, Cl, C(CH₃)₃, —CH(CH₃)₂, —C(CH₃)₂CN,—C(CH₃)₂CF₃, —CF(CH₃)₂, —CF₂(CH₃), —C(CH₃)(CH₂F)₂, —C(CH₃)₂CH₂OCH₃,—C(CH₃)₂CH₂OH, CF₃, —OCH₃, —O(CH₂)₂OCH₃, —O(CH₂)₂CH(CH₃)₂OCH₃,morpholinomethyl, phenyl, cyclopentyl, or

where q is an integer from 1-5.

In one embodiment, R¹¹ is

where each R¹⁰ is independently selected from halo, alkyl, haloalkyl,hydroxyalkyl, haloalkoxy, cycloalkyl, alkoxyalkyl, alkoxyalkoxy, aryl,heterocyclylalkyl and heterocyclylcarbonyl. In one embodiment, each R¹⁰is —F, Cl, C(CH₃)₃, —CH(CH₃)₂, —C(CH₃)₂CN, —C(CH₃)₂CF₃, —CF(CH₃)₂,—CF₂(CH₃), —C(CH₃)(CH₂F)₂, —C(CH₃)₂CH₂OCH₃, —C(CH₃)₂CH₂OH, CF₃, —OCH₃,—O(CH₂)₂OCH₃, —O(CH₂)₂CH(CH₃)₂OCH₃, morpholinomethyl, phenyl,cyclopentyl or

where q is an integer from 1-5.

In one embodiment, R¹¹ is

where each R¹⁰ is independently selected from halo, alkyl, haloalkyl,hydroxyalkyl, haloalkoxy, cycloalkyl, alkoxyalkyl, alkoxyalkoxy, aryl,heterocyclylalkyl and heterocyclylcarbonyl. In one embodiment, R¹⁰ is—F, Cl, C(CH₃)₃, —CH(CH₃)₂₅—C(CH₃)₂CN, —C(CH₃)₂CF₃, —CF(CH₃)₂,—CF₂(CH₃), —C(CH₃)(CH₂F)₂, —C(CH₃)₂CH₂OCH₃, —C(CH₃)₂CH₂OH, CF₃, —OCH₃,—O(CH₂)₂OCH₃, —O(CH₂)₂CH(CH₃)₂OCH₃, morpholinomethyl, phenyl,cyclopentyl or

where q is an integer from 1-5.

In one embodiment, R¹¹ is

where R¹⁰ is as defined elsewhere herein. In one embodiment, R¹⁰ is —F,Cl, C(CH₃)₃, —CH(CH₃)₂, —C(CH₃)₂CN, —C(CH₃)₂CF₃, —CF(CH₃)₂, —CF₂(CH₃),—C(CH₃)(CH₂F)₂, —C(CH₃)₂CH₂OCH₃, —C(CH₃)₂CH₂OH, CF₃, —OCH₃,—O(CH₂)₂OCH₃, —O(CH₂)₂CH(CH₃)₂OCH₃, morpholinomethyl, phenyl,cyclopentyl or

where q is an integer from 1-5.

In one embodiment, the compounds provided herein have formula IX:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein the variables are as described elsewhere herein. In oneembodiment, r is 0, 1 or 2. In one embodiment, X is S(O)_(t) where t isan integer from 0 to 2. In one embodiment, X is S. In one embodiment, Xis O.

In one embodiment, compounds provided have formula IXa:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein the variables are as described elsewhere herein. In oneembodiment, one R¹⁰ is —C(CH₃)₃, —CH(CH₃)₂, —C(CH₃)₂CN, —C(CH₃)₂CF₃,—CF(CH₃)₂, —CF₂(CH₃), —C(CH₃)₂CH₂OH, —C(CH₃)(CH₂F)₂, —C(CH₃)₂CH₂OCH₃,CF₃, phenyl, cyclopentyl or

where q is an integer from 1-5 and the other R¹⁰ is alkoxy, haloalkoxy,alkoxyalkoxy or aminoalkoxy.

In one embodiment, the compounds provided herein have formula X:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein the variables are as described elsewhere herein.

In one embodiment, the compounds provided herein have formula Xa:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein the variables are as described elsewhere herein.

In one embodiment, the compounds provided herein have formula XI:

or pharmaceutically acceptable salts, solvates or hydrates thereof,wherein the variables are as described elsewhere herein.

In one embodiment, each R¹ is selected as follows:

i) each R¹ is absent or is independently selected from the groupconsisting of halo, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, —R⁶OR⁷, —R⁶SR⁷, —R⁶N(R⁷)₂, —R⁶OR⁹OR⁷,—R⁶OR⁹SR⁷, —R⁶SR⁹OR⁷, —R⁶SR⁹SR⁷, —R⁶OR⁹N(R⁷)₂, —R⁶SR⁹N(R⁷)₂, —R⁶CN,—R⁶C(O)R⁷, —R⁶C(O)OR⁷, —R⁶C(O)OR⁹OR⁷, —R⁶C(O)N(R⁷)₂, —R⁶OC(O)N(R⁷)₂ and—R⁶N(R⁷)C(O)R⁸; or

ii) any two adjacent R¹ groups form an alkylenedioxy group,

wherein R¹, R⁶, R⁷ and R⁹ groups are optionally substituted with one,two or three Q¹ groups.

In one embodiment, each R¹ is selected as follows:

i) each R¹ is absent or is independently selected from the groupconsisting of halo, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, —R⁶OR⁷, —R⁶SR⁷, —R⁶N(R⁷)₂, —R⁶OR⁹OR⁷,—R⁶OR⁹SR⁷, —R⁶SR⁹OR⁷, —R⁶SR⁹SR⁷, —R⁶CN, —R⁶C(O)N(R⁷)₂, —R⁶OC(O)N(R⁷)₂and —R⁶N(R⁷)C(O)R⁸; or

ii) any two adjacent R¹ groups form an alkylenedioxy group,

wherein R¹, R⁶, R⁷ and R⁹ groups are optionally substituted with one,two or three Q¹ groups.

In one embodiment, each R¹ is selected as follows:

i) each R¹ is absent or is independently selected from the groupconsisting of halo, nitro, amino, alkyl, cycloalkylalkyl,heterocyclylalkyl, aralkyl, heteroaryl, heteroaralkyl,cycloalkylcarbonylamino, —R⁶OR⁷, —R⁶OR⁹OR⁷ and —R⁶OR⁹N(R⁷)₂, or

ii) any two adjacent R¹ groups form an alkylenedioxy group;

each R⁶ is independently a direct bond, alkylene chain or alkenylenechain;

each R⁷ is independently selected from (i) or (ii) below:

(i) each R⁷ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl, or

(ii) two R⁷ groups together with the N atom to which they are attachedform a heterocyclyl or heteroaryl;

each R⁹ is independently an alkylene chain or an alkenylene chain,

wherein R¹, R⁶, R⁷ and R⁹ groups are optionally substituted with one,two or three Q¹ groups, wherein each Q¹ is independently haloalkyl,alkyl, —R^(u)OR^(x), —R^(u)OR^(u)OR^(x), —R^(u)C(J)OR^(x),—R^(u)S(O)₂R^(w), —R^(u)N(R^(x))S(O)₂R^(w) or —R^(u)N(R^(x))R^(u)S(O)₂R^(w), wherein R^(u) is direct bond or alkylene, R^(x) ishydrogen or alkyl; R^(w) is alkyl and J is O, S or NR^(x).

In one embodiment, each R¹ is absent or is independently selected fromthe group consisting of halo, amino, alkyl, heteroaryl, alkoxy, hydroxy,alkoxyalkoxy and cycloalkylcarbonylamino, wherein each R¹ is optionallysubstituted with one, two or three Q¹ groups, wherein each Q¹ isindependently haloalkyl, alkyl, —R^(u)OR^(x), —R^(u)OR^(u)OR^(x),—R^(u)C(J)OR^(x), —R^(u)S(O)₂R^(w), —R^(u)N(R^(x))S(O)₂R^(w) or—R^(u)N(R^(x))R^(u)S(O)₂R^(w), wherein R^(u) is direct bond or alkylene,R^(x) is hydrogen or alkyl; R^(w) is alkyl and J is O, S or NR^(x).

In one embodiment, each R¹ is absent or is independently selected fromthe group consisting of —R⁶OR⁷, —R⁶SR⁷, —R⁶N(R⁷)₂, —R⁶OR⁹OR⁷⁵—R⁶OR⁹SR⁷,—R⁶SR⁹OR⁷, —R⁶SR⁹SR⁷, —R⁶OR⁹N(R⁷)₂, —R⁶SR⁹N(R⁷)₂, —R⁶CN, —R⁶C(O)R⁷,—R⁶C(O)OR⁷, —R⁶C(O)OR⁹OR⁷, —R⁶C(O)N(R⁷)₂, —R⁶OC(O)N(R⁷)₂ and—R⁶N(R⁷)C(O)R⁸;

each R⁶ is independently a direct bond, alkylene chain or alkenylenechain;

each R⁷ is independently selected from (i) or (ii) below:

(i) each R⁷ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl, or

(ii) two R⁷ groups together with the N atom to which they are attachedform a heterocyclyl or heteroaryl; and

each R⁹ is independently an alkylene chain or an alkenylene chain;

wherein R¹, R⁶, R⁷ and R⁹ groups are optionally substituted with one,two or three Q¹ groups.

In one embodiment, each R¹ is selected from the group consisting of—R⁶OR⁷, —R⁶OR⁹OR⁷ and —R⁶OR⁹N(R⁷)₂;

each R⁶ is independently a direct bond, alkylene chain or alkenylenechain;

each R⁷ is independently selected from (i) or (ii) below:

(i) each R⁷ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl, or

(ii) two R⁷ groups together with the N atom to which they are attachedform a heterocyclyl or heteroaryl;

each R⁹ is independently an alkylene chain or an alkenylene chain,wherein each R¹, R⁶, R⁷ and R⁹ groups are optionally substituted withone, two or three Q¹ groups.

In one embodiment, n is 2, and each R¹ is independently —R⁶OR⁷ or—R⁶OR⁹OR⁷;

each R⁶ is independently a direct bond, alkylene chain or alkenylenechain;

each R⁷ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl, or

each R⁹ is independently an alkylene chain or an alkenylene chain,

wherein each R¹, R⁶, R⁷ and R⁹ groups are optionally substituted withone, two or three Q¹ groups.

In one embodiment, n is 2, one R¹ is —R⁶OR⁷ or —R⁶OR⁹OR⁷ and the otherR¹ is heterocylylalkoxy;

each R⁶ is independently a direct bond, alkylene chain or alkenylenechain;

each R⁷ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl, or

each R⁹ is independently an alkylene chain or an alkenylene chain,

wherein each R¹, R⁶, R⁷ and R⁹ groups are optionally substituted withone, two or three Q¹ groups.

In one embodiment, each R¹ is absent or is independently selected fromthe group consisting of fluoro, amino, methyl, methoxy, ethoxy,methoxyethoxy, ethoxyethoxy, cyclopropylcarbonylamino, furyl, andhydroxy, wherein furyl is substituted with —R^(u)NH R^(u)S(O)₂R^(w),wherein R^(u) is methylene or ethylene and R^(w) is methyl.

In one embodiment, two adjacent R¹ groups form an alkylenedioxy group.In one embodiment, two adjacent R¹ groups form an ethylenedioxy group.

In one embodiment, each R¹ is independently

where each K is independently a direct bond, alkylene, alkenylene oralkynylene;

A is N or CR¹⁶;

Y is —O, —S, —S(O), —S(O)₂, —N(R¹⁴), —C(H)R¹⁵, or —C(O);

p is an integer from 0 to 2;

R¹⁴ is hydrogen, alkyl, haloalkyl, hydroxy(C₂-C₆)alkyl, cycloalkyl,heteroaryl, heteroarylalkyl, aryl, arylalkyl, S(O)_(t)R¹³, —C(O)R¹²,—C(O)OR¹², —C(O)N(R¹²)₂, or —C(O)SR¹²;

R¹⁵ is hydrogen, halo, nitro, cyano, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, —OR¹², —SR¹²,—N(R¹²)₂, —S(O)_(t)R¹³, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)₂, —C(O)SR¹², or—N(R¹²)S(O)_(t)R¹³;

R¹⁶ is hydrogen or alkyl;

t is 1 or 2;

each R¹² is independently selected from a group consisting of hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl;

each R¹³ is independently selected from a group consisting of alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl; and

each K is optionally substituted with one, two or three hydroxy or alkylgroups.

In one embodiment, each R¹ is independently

where K is a direct bond or alkylene, optionally substituted with one ortwo hydroxy groups;

A is N or CH;

Y is —O, —S(O)₂, —N(R¹⁴) or —C(H)R¹⁵;

p is an integer from 0 to 2;

R¹⁴ is hydrogen, alkyl, haloalkyl, hydroxy(C₂-C₆)alkyl or S(O)_(t)R¹³;

R¹⁵ is hydrogen, halo, alkyl, hydroxyalkyl or —OR¹²;

t is 1 or 2;

R¹² is hydrogen or alkyl; and

R¹³ is alkyl.

In certain embodiments, K is ethylene or propylene, optionallysubstituted with hydroxy. In one embodiment, K is a direct bond.

In one embodiment, R¹³ is methyl.

In certain embodiments, R¹⁴ is —H, —OH, —CH₃, —CH₂CF₃, —CH₂CHF₂,—CH₂CH₂OH or S(O)₂CH₃.

In certain embodiments, R¹⁵ is —H, —OH, —CH₃, CH₂OH or —CH₂CH₂OH.

In one embodiment, p is 0 or 1. In one embodiment, p is 0. In oneembodiment, p is 1.

In another aspect, provided herein is a compound of formula XII:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein R^(a) is O or S;

X is O or S;

R^(1a) and R^(1b) are each independently selected from the groupconsisting of —R⁶OR⁷, —R⁶SR⁷, —R⁶N(R⁷)₂, —R⁶OR⁹OR⁷, —R⁶OR⁹SR⁷,—R⁶SR⁹OR⁷, —R⁶SR⁹SR⁷, —R⁶OR⁹N(R⁷)₂, —R⁶SR⁹N(R⁷)₂, —R⁶CN, —R⁶C(O)R⁷,—R⁶C(O)OR⁷, —R⁶C(O)OR⁹OR⁷, —R⁶C(O)N(R⁷)₂, —R⁶OC(O)N(R⁷)₂ and—R⁶N(R⁷)C(O)R⁸;

each R⁶ is a direct bond;

each R⁷ is independently selected from (i) or (ii) below:

(i) each R⁷ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl, or

(ii) two R⁷ groups together with the N atom to which they are attachedform a heterocyclyl or heteroaryl;

each R⁹ is independently an alkylene chain or an alkenylene chain;

wherein R¹, R⁶, R⁷ and R⁹ groups are optionally substituted with one,two or three Q¹ groups; and the other variables are as defined elsewhereherein.

In another aspect, provided herein is a compound of formula XII:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein R^(a) is O or S;

X is O or S;

R^(1a) and R^(1b) are selected as follows:

i) R^(1a) and R^(1b) are each independently selected from hydrogen,halo, amino, alkyl, alkoxy, hydroxy, heteroaryl, alkoxyalkoxy,cycloalkylcarbonylamino and a group of formula:

where each K is independently a direct bond or alkylene;

A is N or CR¹⁶;

Y is —O, —S, —S(O), —S(O)₂, —N(R¹⁴), —C(H)R¹⁵, or —C(O);

p is an integer from 0 to 2;

R¹⁴ is hydrogen, alkyl, haloalkyl, hydroxy(C₂-C₆)alkyl, cycloalkyl,heteroarylalkyl, arylalkyl, S(O)_(t)R¹³ or —C(O)R¹²;

R¹⁵ is hydrogen, halo, alkyl, hydroxyalkyl or —OR¹²;

R¹⁶ is hydrogen or alkyl;

t is 1 or 2;

each R¹² is independently selected from a group consisting of hydrogenor alkyl;

R¹³ is alkyl;

each K is optionally substituted with one, two or three hydroxy or alkylgroups; or

ii) R^(1a) and R^(1b) groups form an alkylenedioxy group;

each R^(1a) and R^(1b) is independently optionally substituted with oneor two Q¹ groups selected from haloalkyl, alkyl, —R^(u)OR^(x),—R^(u)C(J)OR^(x), —R^(u)S(O)₂R^(w), —R^(u)N(R^(x))S(O)₂R^(w) and—R^(u)N(R^(x)) R^(u)S(O)₂R^(w), wherein R^(u) is direct bond oralkylene, R^(x) is hydrogen or alkyl; R^(w) is alkyl and J is O, S orNR^(x); and

the other variables are as defined elsewhere herein.

In one embodiment, at least one of R^(1a) or R^(1b) is other thanhydrogen.

In one embodiment, A is CH. In one embodiment, p is 0 and A is CH.

In one embodiment, R^(1b) is hydrogen and R^(1a) is heteroaryl groupsubstituted with —R^(u)N(R^(x)) R^(u)S(O)₂R^(w), wherein R^(u) is directbond or alkylene, R^(x) is hydrogen or alkyl; R^(w) is alkyl. In oneembodiment, R^(1b) is hydrogen and R^(1a) is furyl substituted with—R^(u)N(R^(x)) R^(u)S(O)₂R^(w), wherein R^(u) is methylene or ethylene,R^(x) is hydrogen and R^(w) is methyl.

In one embodiment, one of R^(1a) and R^(1b) is —OR⁷ where R⁷ is alkyl,haloalkyl, hydroxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl orcycloalkylalkyl; and the other of R^(1a) and R^(1b) is a group offormula

where each K is independently a direct bond or alkylene;

A is N or CR¹⁶;

Y is —O, —S, —S(O), —S(O)₂, —N(R¹⁴), —C(H)R¹⁵, or —C(O);

p is an integer from 0 to 2;

R¹⁴ is hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl,heteroarylalkyl, arylalkyl, S(O)_(t)R¹³ or —C(O)R¹²;

R¹⁵ is hydrogen, halo, alkyl, hydroxyalkyl or —OR¹²;

R¹⁶ is hydrogen or alkyl;

t is 1 or 2;

each R¹² is independently selected from a group consisting of hydrogenor alkyl;

R¹³ is alkyl;

each K is optionally substituted with one, two or three hydroxy or alkylgroups; and

each R^(1a) and R^(1b) is independently optionally substituted with oneor two Q¹ groups described elsewhere herein.

In one embodiment, R^(1a) is —OR⁷ where R⁷ is alkyl, haloalkyl,hydroxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl orcycloalkylalkyl; and R^(1b) is a group of formula

where each K is independently a direct bond or alkylene;

A is N or CR¹⁶;

Y is —O, —S, —S(O), —S(O)₂, —N(R¹⁴), —C(H)R¹⁵, or —C(O);

p is an integer from 0 to 2;

R¹⁴ is hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl,heteroarylalkyl, arylalkyl, S(O)_(t)R¹³ or —C(O)R¹²;

R¹⁵ is hydrogen, halo, alkyl, hydroxyalkyl or —OR¹²;

R¹⁶ is hydrogen or alkyl;

t is 1 or 2;

each R¹² is independently selected from a group consisting of hydrogenor alkyl;

R¹³ is alkyl;

each K is optionally substituted with one, two or three hydroxy or alkylgroups; and

each R^(1a) and R^(1b) is independently optionally substituted with oneor two Q¹ groups described elsewhere herein.

In one embodiment, R^(1b) is —R^(u)OR^(x), and R^(1a) is a group offormula

where each K is independently a direct bond or alkylene;

A is N or CR¹⁶;

Y is —O, —S, —S(O), —S(O)₂, —N(R¹⁴), —C(H)R¹⁵, or —C(O);

p is an integer from 0 to 2;

R¹⁴ is hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl,heteroarylalkyl, arylalkyl, S(O)_(t)R¹³ or —C(O)R¹²;

R¹⁵ is hydrogen, halo, alkyl, hydroxyalkyl or —OR¹²;

R¹⁶ is hydrogen or alkyl;

t is 1 or 2;

each R¹² is independently selected from a group consisting of hydrogenor alkyl;

R¹³ is alkyl;

each K is optionally substituted with one, two or three hydroxy or alkylgroups; and

each R^(1a) and R^(1b) is independently optionally substituted with oneor two Q¹ groups described elsewhere herein.

In another aspect, provided herein is a compound of formula XIII:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein R^(1a) and R^(1b) are selected as follows:

i) R^(1a) and R^(1b) are each independently hydrogen, alkoxy,alkoxyalkoxy, substituted or unsubstituted heteroaryl, or a group offormula:

where K is a direct bond or alkylene, optionally substituted with ahydroxy group;

A is N or CH;

Y is —O—, —S(O)₂—, —N(R¹⁴)— or —C(H)R¹⁵—;

p is an integer from 0 to 2;

R¹⁴ is hydrogen, alkyl, haloalkyl, hydroxy(C₂-C₆)alkyl or S(O)_(t)R¹³;

R¹⁵ is hydrogen, halo, alkyl, hydroxyalkyl or —OR¹²;

t is 1 or 2;

R¹² is hydrogen or alkyl; and

R¹³ is alkyl; or

ii) R^(1a) and R^(1b) groups together form an alkylenedioxy group;

where the substitutents on the heteroaryl, when present, are selectedfrom one two or three groups selected from halo, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkoxy and hydroxyl;

X is O or S;

R³ is halo;

R⁴ and R⁵ are each hydrogen; and

R¹¹ is optionally substituted phenyl, isoxazolyl or pyrazolyl, whereinsubstituents when present are selected from one or two R¹⁰ groups, eachof which is independently selected from hydrogen, halo, alkyl, alkoxy,haloalkoxy, cycloalkyl, alkoxyalkoxy, aryl, heterocyclyl,heterocyclylcarbonyl, alkoxycarbonyl and heteroaryl, where the alkylgroup is optionally substituted with 1 or 2 groups selected from halo,hydroxy, alkoxy, cycloalkyl, heterocyclyl, alkylcarbonyl andalkoxycarbonyl.

In one embodiment, the compound has formula XII or XIII, wherein A is CHand the other variables are as described elsewhere herein. In oneembodiment, the compound has formula XII or XIII, wherein p is 0; A isCH and the other variables are as described elsewhere herein.

In another aspect, provided herein is a compound of formula XIV:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein R^(1c) is hydrogen, halo, alkyl, haloalkyl, alkoxy, alkoxyalkyl,alkoxyalkoxy, heterocyclyloxy or aryl; and the other variables are asdescribed elsewhere herein.

In another aspect, provided herein is a compound of formula XV:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein R^(1d) is hydrogen, halo, alkyl, haloalkyl, alkoxy, alkoxyalkyl,alkoxyalkoxy or aryl; and the other variables are as described elsewhereherein.

In another aspect, provided herein is a compound of formula XVIA orXVIB:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein R^(1a) and R^(1b) are selected from Q¹ and the other variablesare described elsewhere herein. In one embodiment, the compounds haveformula XVIA or XVIB wherein R¹⁰ is selected from hydrogen, halo, alkyl,cyanoalkyl, haloalkyl or cycloalkyl; and the other variables are asdescribed elsewhere herein.

In another aspect, provided herein is a compound of formula XVII:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein the variables are as described elsewhere herein. In oneembodiment, the compounds have formula XVII, wherein X is O or S;

R^(1a) and R^(1b) are selected as follows:

i) R^(1a) and R^(1b) are each independently methoxy, methoxyethoxy,methylsulfonylpropyloxy, or a group of formula:

where K is ethylene or propylene, optionally substituted with a hydroxygroup;

A is N or CH;

Y is —O, —S(O)₂, —N(R¹⁴) or —C(H)R¹⁵;

p is 1;

R¹⁴ is hydrogen, methyl, hydroxyethyl, or methylsulfonyl;

R¹⁵ is hydrogen, hydroxymethyl, hydroxyethyl or hydroxy; and

ii) R^(1a) and R^(1b) groups together with the carbon atoms on whichthey are substituted form an ethylenedioxy group.

In another aspect, provided herein is a compound of formula XVIII:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein X is O or S;

R^(1a) and R^(1b) are selected as follows:

i) R^(1a) and R^(1b) are each independently alkoxy, alkoxyalkoxy,alkylsulfonylalkoxy or a group of formula:

where K is a direct bond or alkylene, optionally substituted with ahydroxy group;

A is N or CH;

Y is —O, —S(O)₂, —N(R¹⁴) or —C(H)R¹⁵;

p is 0 or 1;

R¹⁴ is hydrogen, alkyl, haloalkyl, hydroxy(C₂-C₆)alkyl or S(O)_(t)R¹³;

R¹⁵ is hydrogen, halo, alkyl, hydroxyalkyl or —OR¹²;

t is 1 or 2;

R¹² is hydrogen or alkyl; and

R¹³ is alkyl; or

ii) R^(1a) and R^(1b) groups together form an alkylenedioxy group.

In one embodiment, the compound is of formula XVIII or apharmaceutically acceptable salt, solvate or hydrate thereof, wherein Xis O or S;

R^(1a) and R^(1b) are selected as follows:

i) R^(1a) and R^(1b) are each independently methoxy, methoxyethoxy,methylsulfonylpropyloxy, or a group of formula:

where K is ethylene or propylene, optionally substituted with a hydroxygroup;

A is N or CH;

Y is —O, —S(O)₂, —N(R¹⁴) or —C(H)R¹⁵;

p is 1;

R¹⁴ is hydrogen, methyl, hydroxyethyl, or methylsulfonyl;

R¹⁵ is hydrogen, hydroxymethyl, hydroxyethyl or hydroxy; or

ii) R^(1a) and R^(1b) groups together with the carbon atoms on whichthey are substituted form an ethylenedioxy group.

In another aspect, provided herein is a compound of formula XVII orXVIII or a pharmaceutically acceptable salt, solvate or hydrate thereof,

wherein X is O or S;

R^(1a) and R^(1b) are each independently hydrogen, fluoro, methoxy,ethoxy, methoxyethoxy, or a group of formula:

where K is a direct bond or alkylene;

A is CH;

Y is —O, —S(O)₂, —N(R¹⁴) or —C(H)R¹⁵;

p is 0;

R¹⁴ is hydrogen, alkyl, haloalkyl, hydroxy(C₂-C₆)alkyl or S(O)_(t)R¹³;

R¹⁵ is hydrogen, halo, alkyl, hydroxyalkyl or —OR¹²;

t is 1 or 2;

R¹² is hydrogen or alkyl; and

R¹³ is alkyl.

In another aspect, provided herein is a compound of formula XVII orXVIII or a pharmaceutically acceptable salt, solvate or hydrate thereof,

wherein X is O or S;

at least one of R^(1a) or R^(1b) is hydrogen and the other is hydrogen,fluoro, methoxy, ethoxy, methoxyethoxy or a group of formula:

where K is a direct bond or alkylene;

A is CH;

Y is —O, —S(O)₂, —N(R¹⁴) or —C(H)R¹⁵;

p is 0;

R¹⁴ is hydrogen, alkyl, haloalkyl, hydroxy(C₂-C₆)alkyl or S(O)_(t)R¹³;

R¹⁵ is hydrogen, halo, alkyl, hydroxyalkyl or —OR¹²;

t is 1 or 2;

R¹² is hydrogen or alkyl; and

R¹³ is alkyl.

In another aspect, provided herein is a compound of formula XIX:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein the variables are as described elsewhere herein. In oneembodiment, the compounds have formula XIX, wherein X is O or S;

R^(1a) and R^(1b) are selected as follows:

i) R^(1a) and R^(1b) are each independently methoxy, methoxyethoxy,methylsulfonylpropyloxy, or a group of formula:

where K is ethylene or propylene, optionally substituted with a hydroxygroup;

A is N or CH;

Y is —O, —S(O)₂, —N(R¹⁴) or —C(H)R¹⁵;

p is 1;

R¹⁴ is hydrogen, methyl, hydroxyethyl, or methylsulfonyl;

R¹⁵ is hydrogen, hydroxymethyl, hydroxyethyl or hydroxy; and

ii) R^(1a) and R^(1b) groups together with the carbon atoms on whichthey are substituted form an ethylenedioxy group;

R¹⁰ is selected from hydrogen, halo, alkyl, cyanoalkyl, haloalkyl orcycloalkyl.

In another aspect, provided herein is a compound of formula XX:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein each R¹⁰ is independently selected from halo, alkyl, haloalkyl,hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, alkoxyalkoxy, aryl,heterocyclylalkyl and heterocyclylcarbonyl, where the alkyl group isoptionally substituted with 1 or 2 groups selected from halo, hydroxy,alkoxy, cycloalkyl, heterocyclyl, alkylcarbonyl and alkoxycarbonyl; r isan integer from 0 to 3; and the other variables are as describedelsewhere herein. In one embodiment, each R¹⁰ is independently selectedfrom hydrogen, halo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl andalkoxy and r is 0, 1 or 2.

In another aspect, provided herein is a compound of formula XX or apharmaceutically acceptable salt, solvate or hydrate thereof,

wherein X is O or S;

R^(1a) and R^(1b) are selected as follows:

i) R^(1a) and R^(1b) are each independently alkoxy, alkoxyalkoxy or agroup of formula:

where K is a direct bond or alkylene, optionally substituted with ahydroxy group;

A is N or CH;

Y is —O, —S(O)₂, —N(R¹⁴) or —C(H)R¹⁵;

p is an integer from 0 to 2;

R¹⁴ is hydrogen, alkyl, haloalkyl, hydroxy(C₂-C₆)alkyl or S(O)_(t)R¹³;

R¹⁵ is hydrogen, halo, alkyl, hydroxyalkyl or —OR¹²;

t is 1 or 2;

R¹² is hydrogen or alkyl; and

R¹³ is alkyl; or

ii) R^(1a) and R^(1b) groups together form an alkylenedioxy group; and

r is 0, 1, 2 or 3.

In another aspect, provided herein is a compound of formula XXI:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein X is O or S;

R^(1a) and R^(1b) are selected as follows:

i) R^(1a) and R^(1b) are each independently alkoxy, alkoxyalkoxy,alkylsulfonylalkoxy or a group of formula:

where K is a direct bond or alkylene, optionally substituted with ahydroxy group;

A is N or CH;

Y is —O, —S(O)₂, —N(R¹⁴) or —C(H)R¹⁵;

p is 0 or 1;

R¹⁴ is hydrogen, alkyl, haloalkyl, hydroxy(C₂-C₆)alkyl or S(O)_(t)R¹³;

R¹⁵ is hydrogen, halo, alkyl, hydroxyalkyl or —OR¹²;

t is 1 or 2;

R¹² is hydrogen or alkyl; and

R¹³ is alkyl; or

ii) R^(1a) and R^(1b) groups together form an alkylenedioxy group

each R¹⁰ is independently selected from alkyl, haloalkyl, hydroxyalkyl,aryl, haloaryl, alkylaryl or heteroaryl.

In another aspect, provided herein is a compound of formula XXII:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein X is O or S;

R^(1a) and R^(1b) are selected as follows:

i) R^(1a) and R^(1b) are each independently alkoxy, alkoxyalkoxy,alkylsulfonylalkoxy or a group of formula:

where K is a direct bond or alkylene, optionally substituted with ahydroxy group;

A is N or CH;

Y is —O, —S(O)₂, —N(R¹⁴) or —C(H)R¹⁵;

p is 0 or 1;

R¹⁴ is hydrogen, alkyl, haloalkyl, hydroxy(C₂-C₆)alkyl or S(O)_(t)R¹³;

R¹⁵ is hydrogen, halo, alkyl, hydroxyalkyl or —OR¹²;

t is 1 or 2;

R¹² is hydrogen or alkyl; and

R¹³ is alkyl; or

ii) R^(1a) and R^(1b) groups together form an alkylenedioxy group eachR¹⁰ is independently selected from alkyl, haloalkyl, hydroxyalkyl, aryl,haloaryl, alkylaryl or heteroaryl.

In one embodiment, the compound has formula XXI or XXII or apharmaceutically acceptable salt, solvate or hydrate thereof, whereineach R¹⁰ is independently selected from tert-butyl, methyl, trifluorotert-butyl, phenyl, p-fluorophenyl or p-methylphenyl.

In one embodiment, the compound is selected from formula XVI-XXIII,wherein p is 0; A is CH and the other variables are as describedelsewhere herein.

In one embodiment, the compound is selected from a group consisting ofthe compounds in Table 1.

Certain exemplary compounds are provided in Table 1.

TABLE 1 A375 BRAF BRAF pMEK Viability V600E WT RAF IC50 EC50 Kd Kd 1 KdName (nM) (nM) (nM) nM nM S35

Ex 1 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6,7- dimethoxy-quinazolin-4- yloxy) phenyl) urea A C A D B C

Ex 2 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6- methoxy- quinazolin-4-yloxyphenyl) urea ND ND ND ND ND ND

Ex 3 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- quinazolin-4-yloxy)phenyl) urea ND ND ND ND ND ND

Ex 4 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6,7-difluoro- quinazolin-4-yloxy)phenyl) urea ND ND ND ND ND ND

Ex 5 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (5- methyl- quinazolin-4-yloxy)phenyl) urea ND ND ND ND ND ND

Ex 6 1-(5-tert- butylisoxazol- 3-yl)-3-[3- (7-ethoxy-6- methoxy-quinazolin-4- yloxy) phenyl] urea hydrochloride A B A D C D

Ex 7 1-(5-tert- Butylisoxazol- 3-yl)-3-{3- [6-methoxy- 7-(2- methoxy-ethoxy) quinazolin- 4- yloxy] phenyl} urea hydrochloride A B A B B D

Ex 8 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6- methyl- quinazolin-4-yloxy) phenyl) urea ND ND ND ND ND ND

Ex 9 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6,7- dimethoxy-quinazolin-4- yloxy)-4- fluorophenyl) urea A A A D C D

Ex 10 1-(5-tert- butylisoxazol- 3-yl)-3-(4- chloro-3- (6,7- dimethoxy-quinazolin-4-yl oxy)phenyl) urea D D C D D C

Ex 11 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-ethoxy-7- methoxy-quinazolin-4- yloxy)phenyl) urea A A A D C C

Ex 12 1-{3-[6,7- bis(2- methoxy- ethoxy) quinazolin-4- yloxy]phenyl}-3-(5-tert- butylisoxazol- 3-yl)urea hydrochloride A B A C B C

Ex 13 1-(5-tert- Butylisoxazol- 3-yl)-3-[3- (6,7- diethoxy-quinazolin-4- yloxy)phenyl] urea hydrochloride B C B D D C

Ex 14 1-(5-tert- Butylisoxazol- 3-yl)-3-[3- (7,8-dihydro- [1,4]dioxino[2,3- g]quinazolin- 4-yloxy) phenyl]urea hydrochloride C D A C B C

Ex 15 1-(5-tert- butylisoxazol- 3-yl)-3-{3- [7-methoxy- 6-(2- methoxy-ethoxy) quinazolin-4- yloxy]phenyl} urea hydrochloride A A A B B C

Ex 16 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(2-(piperidin-1- yl)ethoxy) quinazolin-4- yloxy)phenyl) urea B D A C D C

Ex 17 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-(2-(4- (hydroxy- methyl)piperidin- 1-yl)ethoxy)-7- methoxy- quinazolin-4- yloxy)phenyl) urea B BA C C C

Ex 18 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(2-(4- methyl-piperazin-1- yl)ethoxy) quinazolin-4- yloxy)phenyl) urea A B A B C D

Ex 19 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-(2-(4-(2- hydroxyethyl)piperazin-1- yl)ethoxy)-7- methoxy- quinazolin-4- yloxy)phenyl) urea A BA B B D

Ex 20 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(2-morpholino- ethoxy) quinazolin-4- yloxy)phenyl) urea A A A B B C

Ex 21 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(3-(4- methylpiperazin-1- yl)propoxy) quinazolin-4- yloxy)phenyl) urea A B A B B D

Ex 22 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(3-morpholino- propoxy) quinazolin-4- yloxy)phenyl) urea A A A A A D

Ex 23 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(3-(piperidin-1- yl)propoxy) quinazolin-4- yloxy)phenyl) urea A C A C C D

Ex 24 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-(3-(4- (hydroxy- methyl)piperidin- 1- yl)propoxy)- 7- methoxy- quinazolin-4- yloxy)phenyl) ureaA C A C C D

Ex 25 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(3-(4-(methyl- sulfonyl) piperazin- 1- yl)propoxy) quinazolin-4- yloxy)phenyl)urea A A A B B D

Ex 26 1-(5-tert- butyl- isoxazol-3- yl)-3-(3-{6- [3-(1,1- dioxo-thiomorpholin- 4-yl)- propoxy]-7- methoxy- quinazolin-4- yloxy}-phenyl)-urea A A A B A D

Ex 27 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-methoxy- 7-(3-morpholino- propoxy) quinazolin-4- yloxy)phenyl) urea A A A B B D

Ex 28 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-methoxy- 7-(3-(4- methyl-piperazin-1- yl)propoxy) quinazolin-4- yloxy)phenyl) urea A A A B A D

Ex 29 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-(3-(4- hydroxymethyl)piprridin- 1- yl)propoxy)- 6- methoxy- quinazolin-4- yloxy)phenyl) ureaA A A B B D

Ex 30 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-(3-(4-(2- hydroxyethyl)piperazin-1- yl)propoxy)- 6-methoxy quinazolin-4- yloxy)phenyl) urea A AA A B D

Ex 31 1-(5-tert- butyl- isoxazol-3- yl)-3-(3-{7- [3-(3- hydroxy-pyrrolidin-1- yl)- propoxy]-6- methoxy- quinazolin-4- yloxy}-phenyl)-urea A A A B B D

Ex 32 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-methoxy- 7-(3-(4- (methylsulfonyl) piperazin-1- yl)propoxy) quinazolin-4- yloxy)phenyl) urea A BA C B D

Ex 33 (S)-1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-(3-(3- hydroxy-pyrrolidin-1- yl)propoxy)- 6- methoxy- quinazolin-4- yloxy)phenyl) ureaA A A B B D*

Ex 34 (R)-1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-(3-(3- hydroxy-pyrrolidin-1- yl)propoxy)- 6- methoxy- quinazolin-4- yloxy)phenyl) ureaA D A B B D*

Ex 35 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-methoxy- 7-(2-morpholino- ethoxy) quinazolin-4- yloxy) phenyl)urea A C A B B C

Ex 36 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-methoxy- 7-(2-(4- methylpiperazin-1- yl)ethoxy) quinazolin-4- yloxy)phenyl) urea A B A B B C

Ex 37 1-(5-tert- Butyl- isoxazol-3- yl)-3-(3-{7- [2-(4- hydroxy- methyl-piperidin- 1-yl)- ethoxy]-6- methoxy- quinazolin-4- yloxy}- phenyl)-ureaA B A B B C

Ex 38 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-(2-(4-(2- hydroxyethyl)piperazin-1- yl) ethoxy)-6 methoxy- quinazolin- 4yloxy) phenyl) urea A BA B B D

Ex 39 1-(5-tert- Butyl- isoxazol-3- yl)-3-(3-{7- [2-(1,1- dioxo-1l6-thiomoipholin- 4-yl)- ethoxy]-6- methoxy- quinazolin-4- yloxy}-phenyl)-urea A A A B B C

Ex 40 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-(2- methoxyethoxy)quinazolin- 4- yloxy)phenyl) urea A C A D B C

Ex 41 1-(5-tert- Butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(3-(methylsulfonyl) propoxy) quinazolin-4- ylthio)phenyl) urea A A A A A C

Ex 42 1-(3-(2- fluoropropan- 2- yl)isoxazol- 5-yl)-3-(3- (7-methoxy-6-(3- (methylsulfonyl) propoxy) quinazolin-4- yloxy)phenyl) urea B C A AA C*

Ex 43 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-(2- methoxyethoxy)quinazolin- 4- yloxy)phenyl) urea B D A C B C

Ex 44 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(3-(methylsulfonyl) propoxy) quinazolin-4- ylthio)phenyl) urea A B A A A C

Ex 45 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(2-methoxyethoxy) quinazolin- 4- ylthio)phenyl) urea A B A C B C

Ex 46 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6,7- dimethoxy-quinazolin-4- ylthio)phenyl) urea A B A C B C

Ex 47 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6,7- difluoro-quinazolin-4- ylthio)phenyl) urea D D C D D A

Ex 48 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7- methoxy- quinazolin-4-ylthio)phenyl) urea C D B D D C

Ex 49 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6- methoxy- quinazolin-4-ylthio)phenyl) urea C D B D C C

Ex 50 1-(5-tert- Butylisoxazol- 3-yl)-3-[3- (7-ethoxy-6- methoxy-quinazolin-4- ylthio)phenyl] urea B D B C B B

Ex 51 1-(5-tert- butylisoxazol- 3-yl)-3-[3- (6,7- diethoxy-quinazolin-4- ylthio)phenyl] urea B D C D D C

Ex 52 1-(5-tert- butylisoxazol- 3-yl)-3-{3- [6-methoxy- 7-(2-methoxyethoxy) quinazolin- 4- ylthio]phenyl} urea hydrochloride A C A BB C

Ex 53 1-{3-[6,7- bis(2- methoxyethoxy) quinazolin- 4- ylthio]phenyl}-3-(5-tert- butylisoxazol- 3-yl)urea hydrochloride A C A C B C

Ex 54 1-(5-tert- butylisoxazol- 3-yl)-3-[3- (7,8-dihydro- [1,4]dioxino[2,3- g]quinazolin- 4-ylthio) phenyl]urea hydrochloride C D C D D C

Ex 55 1-(5-tert- Butylisoxazol- 3-yl)-3-{3- [7-methoxy- 5- (tetrahydro-2H-pyran-4- ylthio) quinazolin- 4-yloxy] phenyl}urea A B A C B C

Ex 56 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-ethoxy-7- methoxy-quinazolin-4- ylthio)phenyl) urea A A A C B B

Ex 57 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(3-(piperidin-1- yl)propoxy) quinazolin-4- ylthio)phenyl) urea A D A C C C

Ex 58 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-(3-(4- (hydroxymethyl)piperidin- 1- yl)propoxy)- 7- methoxy- quinazolin-4- ylthio)phenyl) ureaA D A B C D

Ex 59 1-(5-tert- Butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(3-(4- methyl-piperazin- 1- yl)propoxy) quinazolin-4- ylthio)phenyl) urea A D A B B D

Ex 60 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(3-(4-(methyl- sulfonyl) piperazin- 1- yl)propoxy) quinazolin-4-ylthio)phenyl) urea A B A C B C

Ex 61 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-(3-(4-(2- hydroxyethyl)piperazin-1- yl)propoxy)- 7- methoxy- quinazolin-4- ylthio)phenyl) ureaD D A B A D

Ex 62 1-(5-tert- butyl- isoxazol-3- yl)-3-(3-{6- [3-(1,1- dioxo-thiomorpholin- 4-yl)- propoxy]-7- methoxy- quinazolin-4- ylsulfanyl}-phenyl)-urea A A A B A C

Ex 63 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(3-morpholino- propoxy) quinazolin-4- ylthio) phenyl)urea A C A B A C

Ex 64 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(3-(methylsulfonyl) propoxy) quinazolin-4- ylthio)phenyl) urea A B A A A C

Ex 65 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(2-(piperidin-1- yl)ethoxy) quinazolin-4- ylthio)phenyl) urea B D A D C C

Ex 66 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-(2-(4- (hydroxymethyl)piperidin- 1- yl)ethoxy)-7- methoxy- quinazolin-4- ylthio)phenyl) urea AD A C C C

Ex 67 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(2-(4- methyl-piperazin-1- yl)ethoxy) quinazolin-4- ylthio)phenyl) urea A D A B B C

Ex 68 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-(2-(4-(2- hydroxyethyl)piperazin-1- yl)ethoxy)-7- methoxy- quinazolin-4- ylthio) phenyl)urea AC A B B C

Ex 69 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(2-(4-(methylsulfonyl) piperazin-1- yl)ethoxy) quinazolin-4- ylthio)phenyl)urea A B A B B C

Ex 70 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(2-morpholino- ethoxy) quinazolin- 4-ylthio) phenyl)urea A A A B A C

Ex 71 1-(5-tert- butyl- isoxazol-3- yl)-3-(3-{6- [2-(1,1- dioxo-thiomorpholin- 4-yl)- ethoxy]-7- methoxy- quinazolin-4- ylsulfanyl}-phenyl)-urea A B A A A C

Ex 72 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-methoxy- 7-(2-morpholino- ethoxy) quinazolin-4- ylthio) phenyl) urea A C A C B D

Ex 73 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-methoxy- 7-(3-(4- methyl-piperazin-1- yl)propoxy) quinazolin-4- ylthio)phenyl) urea A C A B B D

Ex 74 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-(3-(4- (hydroxylmethyl)piperidin-1- yl)propoxy)- 6-methoxy- quinazolin-4- ylthio)phenyl) urea AB A B A D

Ex 75 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-(3-(4-(2- hydroxyethyl)piperazin-1- yl)propoxy)- 6-methoxy- quinazolin-4- ylthio)phenyl) urea AD A B B D

Ex 76 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-methoxy-7-(3-(piperidin-1- yl)propoxy) quinazolin-4- ylthio)phenyl) urea A D A BC D

Ex 77 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-methoxy- 7-(3-(4-(methylsulfonyl) piperazin-1- yl)propoxy) quinazolin-4- ylthio)phenyl)urea A B A C C D

Ex 79 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-methoxy- 7-(2-morpholino- ethoxy) quinazolin-4- ylthio) phenyl)urea A D A C C D

Ex 80 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-methoxy- 7-(2-(piperidin-1- yl)ethoxy) quinazolin-4- ylthio)phenyl) urea B D A B B C

Ex 81 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-methoxy- 7-(2-(4-(methyl- sulfonyl) piperazin-1-yl) ethoxy) quinazolin-4- ylthio)phenyl)urea A B A C C C

Ex 83 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-methoxy- 7-(2-(4- methyl-piperazin-1- yl)ethoxy) quinazolin-4- ylthio)phenyl) urea A D A B B C

Ex 84 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-(2-(4-(2- hydroxyethyl)piperazin-1- yl)ethoxy)-6- methoxy- quinazolin-4- ylthio) phenyl)urea AD A B B D

Ex 86 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-(2-(4- (hydroxymethyl)piperidin- 1- yl)ethoxy)-6- methoxy- quinazolin-4- ylthio)phenyl) urea AD B D C C

Ex 87 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-(2- methoxyethoxy)quinazolin- 4- ylthio)phenyl) urea B D B D C C

Ex 88 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(2-(methylsulfonyl) ethoxy) quinazolin-4- ylthio)phenyl urea A C A A A C

Ex 89 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (2-chloro-6,7- dimethoxy-quinazolin-4- ylthio) phenyl)urea D ND D D D A

Ex 90 1-(5-tert- Butyl- isoxazol-3- yl)-3-(3-{6- [3-(1,1- dioxo--thiomorpholin- 4-yl)- propoxy]- quinazolin-4- ylsulfanyl}- phenyl)-ureaA D A C B C

Ex 91 1-(5-tert- Butyl- isoxazol-3- yl)-3-(3-{6- [2-(1,1- dioxo-1l6-thiomorpholin- 4-yl)- ethoxy]-7- methoxy- quinazolin-4- yloxy}-phenyl)-urea A A A B B C

Ex 92 1-(5-tert- butylisoxazol- 3-yl)-3-{3- [6-(5-{[2- (methylsulfonyl)ethylamino] methyl} furan-2- yl)quinazolin- 4- yloxy]phenyl} urea A A AC B C

Ex 94 1-(5-tert- butylisoxazol- 3-yl)-3-{3- [7-methoxy- 5- (tetrahydro-2H-pyran-4- yloxy) quinazolin-4- yloxy]phenyl} urea B D B D B C

Ex 95 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-hydroxy- 6- methoxy-quinazolin-4- yloxy)phenyl) urea A A A C B C

Ex 96 (S)-1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-methoxy-7-(pyrrolidin- 3-yloxy) quinazolin-4- yloxy)phenyl) urea B D A B A C

Ex 97 (S)-1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-methoxy- 7-(1-methylpyrrolidin- 3-yloxy) quinazolin-4- yloxy)phenyl) urea mono acetateB D A B C C

Ex 98 (R)-1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-methoxy- 7-(pyrrolidin- 3-yloxy) quinazolin-4- yloxy)phenyl) urea carboxylate C D AB A C

Ex 99 (R)-1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-methoxy- 7-(1-methylpyrrolidin- 3-yloxy) quinazolin-4- yloxy)phenyl) urea mono acetateB D A B B C

Ex 100 (R)-1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-(2- hydroxy-3- (4-methylpiperazin- 1- yl)propoxy)- 6-methoxy- quinazolin-4- yloxy)phenyl)urea A A A A A D

Ex 101 1-(3-tert- Butylisoxazol- 5-yl)-3-(3- (6-methoxy- 7-(piperidin-4- ylmethoxy) quinazolin-4- yloxy)phenyl) urea A C A A B C

Ex 102 1-(3-tert- butylisoxazol- 5-yl)-3-(3- (6-methoxy- 7-((1-methylpiperidin- 4- yl)methoxy) quinazolin-4- yloxy)phenyl) urea A A A AB D

Ex 103 (S)-1-(5-tert- butylisoxazol- 3-yl)-3-(3- {7-[1-(2,2-difluoroethyl) pyrrolidin- 3-yloxy]-6- methoxy- quinazolin-4-yloxy}phenyl) urea C D B D D C*

Ex 104 (S)-1-(5-tert- Butylisoxazol- 3-yl)-3-(3- {6-methoxy-7-[1-(2,2,2- trifluoroethyl) pyrrolidin- 3- yloxy] quinazolin-4-yloxy}phenyl) urea C D D D D B*

Ex 105 1-(5-tert- butylisoxazol- 3-yl)-3-(3- {7-[1-(2,2- difluoroethyl)piperidin-4- yloxy]-6- methoxy- quinazolin-4- yloxy}phenyl) urea D D D DD C*

Ex 107 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-hydroxy- 7- methoxy-quinazolin-4- yloxy)phenyl) urea A B A B A C

Ex 108 (S)-tert-butyl 3-(4-(3-(3- (5-tert- butylisoxazole- 3- yl)ureido)phenoxy)-7- methoxy- quinazolin-6- yloxy) pyrrolidine-1- carboxylate A CC D D C

Ex 109 (S)-1-(5-tert- butylisoxazol- 3-yl)-3-(3- (7-methoxy- 6-(1-methylpyrrolidin- 3- yloxy) quinazolin-4- yloxy)phenyl) urea A B A B A D

Ex 110 (S)-1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-(1-(2,2-difluoroethyl) pyrrolidin- 3-yloxy)-7- methoxy- quinazolin-4-yloxy)phenyl) urea A A A B A C

Ex 111 (S)-1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-(2- hydroxy-3-(4methyl- piperazin- 1- yl)propoxy)- 7- methoxy- quinazolin-4-yloxy)phenyl) urea A B A B A D

Ex 112 (R)-1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6-(2- hydroxy-3-(4methyl- piperazin-1- yl)propoxy)- 7- methoxy- quinazolin-4-yloxy)phenyl) urea B C A C B D

Ex 113 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(5-phenylisoxazol- 3-yl)urea C D B C A B

Ex 115 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(3-methoxy-5- (trifluoromethyl) phenyl) urea D D B C B C

Ex 116 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-methoxy-5- (trifluoromethyl) phenyl) urea D D B C B B

Ex 117 1-(3-(6- methoxy-7- (2- methoxyethoxy) quinazolin- 4-yloxy)phenyl)- 3-(3-(2- methoxyethoxy)- 5- (trifluoromethyl) phenyl)urea D D B C B C

Ex 118 1-(3-tert- butylphenyl)- 3-(3-(6,7- dimethoxy- quinazolin-4-yloxy)phenyl) urea B D A B A C*

Ex 119 1-(3-tert- butylphenyl)- 3-(3-(6- methoxy-7- (2- methoxyethoxy)quinazolin- 4- yloxy)phenyl) urea B D A B B C*

Ex 120 1-(3-tert- butylphenyl)- 3-(3-(6,7- dimethoxy- quinazolin-4-ylthio)phenyl) urea B D A B A C*

Ex 122 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-isopropyl- isoxazol- 5- yl)urea B D A A A C

Ex 123 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-(tetrahydro- 2H-pyran-4- yl)isoxazol- 5-yl)urea D D B D C B

Ex 124 1-(3- cyclopropyl- isoxazol-5- yl)-3-(3-(6,7- dimethoxy-quinazolin-4- yloxy)phenyl) urea D D A A A C

Ex 125 1-(3-(2- cyanopropan- 2- yl)isoxazol- 5-yl)-3-(3- (6,7-dimethoxy- quinazolin-4- yloxy)phenyl) urea B D A B B C*

Ex 126 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-(2-fluoropropan- 2- yl)isoxazol- 5-yl)urea A C A B A C

Ex 127 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(5-(1-methyl- cyclopropyl) isoxazol-3- yl)urea B D A A A C

Ex 128 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-(1-methoxy-2- methylpropan- 2- yl)isoxazol- 5-yl)urea C D A D D C*

Ex 129 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-(2-methoxyethoxy)- 5- (trifluoromethyl) phenyl) urea D D B D B B

Ex 130 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(5-(1-methoxy-2- methylpropan- 2- yl)isoxazol- 3-yl)urea B D B D D C

Ex 131 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(5-(1-hydroxy-2- methylpropan- 2- yl)isoxazol- 3-yl)urea C D A B A C

Ex 132 1-(3-tert- butylisoxazol- 5-yl)-3-(3- (6,7- dimethoxy-quinazolin-4- yloxy)phenyl) urea A A A C C C

Ex 133 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(5-isopropyl- isoxazol-3- yl)urea B C A A A C*

Ex 134 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(5-isopropyl- isoxazol-3- yl)urea B D A A A C*

Ex 135 1-(5- cyclopentyl- isoxazol-3-yl)- 3-(3-(6,7- dimethoxy-quinazolin-4- yloxy)phenyl) urea A B A A A C*

Ex 136 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(5-(2-fluoropropan- 2- yl)isoxazol- 3-yl)urea A B A A A C*

Ex 137 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(1-phenyl-3-(1- (trifluoromethyl) cyclo- propyl)- 1H- pyrazol-5-yl) urea AC C D D D*

Ex 138 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(4-methoxy-3- (trifluoromethyl) phenyl) urea B D A B A B

Ex 139 1-(4- methoxy-3- (trifluoromethyl) phenyl)- 3-(3-(6- methoxy-7-(2- methoxyethoxy) quinazolin- 4- yloxy)phenyl) urea B D A A A C*

Ex 140 1-(3-chloro- 5- (trifluoromethyl) phenyl)- 3-(3-(6,7- dimethoxy-quinazolin-4- yloxy) phenyl)urea D D C D C B

Ex 141 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(4-(trifluoromethyl) pyridin- 2-yl)urea C D A A A C

Ex 142 1-(2-chloro- 5- (trifluoromethyl) phenyl)- 3-(3-(6,7- dimethoxy-quinazolin-4- yloxy)phenyl) urea D D B D B B

Ex 143 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(4-(tiifluoromethyl) pyrimidin- 2- yl)urea D D B D B A

Ex 144 1-(3-(6,7- dimethoxy- quinazolin- 4-yloxy)phenyl)- 3-(3-isopropyl- phenyl)urea B D A B A C*

Ex 146 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(6-(trifluoromethyl) pyrimidin- 4-yl)urea D D A B B B*

Ex 147 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-(2-methoxyethoxy)- 4- (trifluoromethyl) phenyl) urea D D B D C B*

Ex 148 1-(3-(6,7- Dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(3-(2-methoxyethoxy)- 4- (trifluoromethyl) phenyl) urea D D C D D B*

Ex 149 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-(morpholine- 4-carbonyl)- 5- (trifluoromethyl) phenyl) urea D D C D D B*

Ex 150 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-fluoro-4- (trifluoromethyl) phenyl) urea D D B C C C*

Ex 151 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-(morpholino- methyl)- 5- (trifluoromethyl) phenyl) urea D D A D B C*

Ex 152 1-(3-(1,1- difluoroethyl) isoxazol-5- yl)-3-(3-(6,7- dimethoxy-quinazolin-4- yloxy)phenyl) urea C C A B B C*

Ex 153 1-(3-tert- butyl-1- phenyl-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND C D D D*

Ex 154 1-(3-tert- butyl-1- phenyl-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- ylthio)phenyl) urea A ND D D D D*

Ex 155 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-(1-(trifluoromethyl) cyclobutyl) isoxazol- 5-yl)urea B D B D D C*

Ex 156 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(3-(1-(trifluoromethyl) cyclobutyl) isoxazol- 5-yl)urea C D C D D C*

Ex 157 1-(3-tert- butyl-1- methyl-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- ylthio)phenyl) urea A D A C B C*

Ex 158 1-(3-tert- butyl-1- methyl-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- yloxy)phenyl) urea B D A D C C*

Ex 159 1-[3-(1,3- difluoro-2- methylpropan- 2- yl)isoxazol- 5-yl]-3-[3-(6,7- dimethoxy- quinazolin-4- yloxy]phenyl) urea B D B C C D*

Ex 160 1-[3-(1,3- difluoro-2- methylpropan- 2- yl)isoxazol- 5-yl]-3-[3-(6,7- dimethoxy- quinazolin-4- ylthio]phenyl) urea A D A C B C*

Ex 161 1-[3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl]- 3-[1-phenyl-3- (trifluoromethyl)- 1H- pyrazol-5- yl]urea A B C D D C*

Ex 162 1-[5-(1,3- difluoro-2- methylpropan- 2- yl)isoxazol- 3-yl]-3-[3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl] urea A A A B A C*

Ex 163 1-(3- cyclopentyl- isoxazol-5-yl)- 3-(3-(6,7- dimethoxy-quinazolin-4- yloxy)phenyl) urea D D B D C C*

Ex 164 1-[3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl]- 3-[1-methyl-3- (trifluoromethyl)- 1H- pyrazol-5- yl]urea B D A A A C*

Ex 165 1-[3-(6,7- dimethoxy- quinazolin-4- yloxy) phenyl]-3-[1-methyl-5- (trifluoromethyl)- 1H- pyrazol-3- yl]urea B C A A A C*

Ex 166 ethyl 2-(3- tert-butyl-5- {3-[3-(6,7- dimethoxy- quinazolin-4-yloxy)phenyl] ureido}-1H- pyrazol-1- yl)acetate C D B D D C*

Ex 167 1-[3-(1,3- difluoro-2- methylpropan- 2-yl)-1- phenyl-1H-pyrazol-5- yl]-3-[3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl] urea AC D D D D*

Ex 168 1-[3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl]- 3-[3-(2-ethoxypropan- 2-yl)-1- phenyl-1H- pyrazol-5- yl]urea A D C D D C*

Ex 169 1-[3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl]- 3-[1-phenyl-5- (trifluoromethyl)- 1H- pyrazol-3- yl]urea B D B D C C*

Ex 170 1-[3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl]- 3-[1-phenyl-5- (trifluoromethyl)- 1H- pyrazol-3- yl]urea B B D D D B*

Ex 171 1-[3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl]- 3-[1-(4-fluorophenyl)- 3- (trifluoromethyl)- 1H- pyrazol-5- yl]urea B B C D D C*

Ex 172 1-[3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl]- 3-[1-p-tolyl-3- (trifluoromethyl)- 1H- pyrazol-5- yl]urea A A C D D C*

Ex 173 1-(4-tert- butylphenyl)- 3-(3-(6,7- dimethoxy- quinazolin-4-yloxy)phenyl) urea B D A C B C

Ex 174 1-(4-tert- butylphenyl)- 3-(3-(6,7- dimethoxy- quinazolin-4-ylthio)phenyl) urea D D B D B C

Ex 175 1-(4- chlorophenyl)- 3-(3-(6,7- dimethoxy- quinazolin-4-yloxy)phenyl) urea D D A A A C

Ex 176 1-(4-chloro- 3- (trifluoromethyl) phenyl)- 3-(3-(6,7- dimethoxy-quinazolin-4- yloxy)phenyl) urea B D A C B C

Ex 177 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(4-(trifluoro- methoxy) phenyl) urea D D A B A C

Ex 178 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-methoxyphenyl) urea D D A C B B*

Ex 179 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-ethoxyphenyl) urea D D A C B B*

Ex 180 1-(3-chloro- 4- methoxyphenyl)- 3-(3- (6,7- dimethoxy-quinazolin-4- yloxy)phenyl) urea D D A A A B*

Ex 181 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-(trifluoromethyl) phenyl) urea D D A A A C*

Ex 182 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3- phenylureaD D D D D B

Ex 183 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(4-(trifluoromethyl) phenyl) urea C D A B A C*

Ex 184 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(4-(trifluoromethyl) phenyl) urea B C B C B C*

Ex 185 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(3-(trifluoromethyl) phenyl) urea C D A B A C*

Ex 186 1-(4-chloro- 3- (trifluoromethyl) phenyl)- 3-(3-(6,7- dimethoxy-quinazolin-4- ylthio)phenyl) urea B C B D D B*

Ex 187 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(3-(2-fluoropropan- 2- yl)isoxazol- 5-yl)urea A D A B A C*

Ex 188 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(3-fluoro-4- (trifluoromethyl) phenyl) urea D D B D C B*

Ex 189 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(3-(morpholino- methyl)-5- (trifluoromethyl) phenyl) urea C C B D C C*

Ex 190 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(3-methoxy-4- (trifluoromethyl) phenyl) urea D D C D D B*

Ex 191 1-[5-(1,3- difluoro-2- methylpropan- 2- yl)isoxazol- 3-yl]-3-[3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl] urea A A A B A C*

Ex 192 1-[3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl]- 3-[1-phenyl-3- (trifluoromethyl)- 1H- pyrazol-5- yl]urea A B C D D C*

Ex 193 1-[3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl]- 3-[1-methyl-3- (trifluoromethyl)- 1H- pyrazol-5- yl]urea A C A A A D*

Ex 194 1-[3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl]- 3-[1-methyl-5- (trifluoromethyl)- 1H- pyrazol-3- yl]urea B C A A A C*

Ex 195 ethyl 2-(3- tert-butyl-5- {3-[3-(6,7- dimethoxy- quinazolin-4-ylthio)phenyl] ureido}-1H- pyrazol-1- yl)acetate B D B D D C*

Ex 196 1-[3-(1,3- difluoro-2- methylpropan- 2-yl)-1- phenyl-1H-pyrazol-5- yl]-3-[3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl] urea AD D D D D*

Ex 197 1-[3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl]- 3-[3-(2-ethoxypropan- 2-yl)-1- phenyl-1H- pyrazol-5- yl]urea B D B D D C*

Ex 198 1-[3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl]- 3-[1-(4-fluorophenyl)- 3- (trifluoromethyl)- 1H- pyrazol-5- yl]urea B C C D D C*

Ex 199 1-[3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl]- 3-[1-p-tolyl-3- (trifluoromethyl)- 1H- pyrazol-5- yl]urea A D D D D D*

Ex 200 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(3-(2-methoxyethoxy)- 5- (trifluoromethyl) phenyl) urea D D C C D C

Ex 201 1-(5- cyclopentyl- isoxazol-3-yl)- 3-(3-(6,7- dimethoxy-quinazolin-4- ylthio)phenyl) urea B D A B A C*

Ex 202 1-(3-tert- butylisoxazol- 5-yl)-3-(3- (6-methoxy- 7-(2-methoxyethoxy) quinazolin- 4- yloxy)phenyl) urea A D A B B C

Ex 203 1-(3-(6- Methoxy-7- (2- methoxyethoxy) quinazolin- 4-yloxy)phenyl)- 3-(5- phenylisoxazol- 3-yl)urea D D D D D B

Ex 205 1-(3-(6- methoxy-7- (2- methoxyethoxy) quinazolin- 4-yloxy)phenyl)- 3-(3- (morpholine- 4-carbonyl)- 5- (trifluoromethyl)phenyl) urea D D B D D C*

Ex 206 1-(5- isopropyl- isoxazol-3-yl)- 3-(3-(6- methoxy-7- (2-methoxyethoxy) quinazolin- 4- yloxy)phenyl) urea C D A A A C*

Ex 207 1-(3- cyclopentyl- isoxazol-5-yl)- 3-(3-(6- methoxy-7- (2-methoxyethoxy) quinazolin- 4- yloxy)phenyl) urea D D A C B C*

Ex 208 1-{3-[6- methoxy-7- (2- methoxyethoxy) quinazolin- 4-yloxy]phenyl}- 3-[1- methyl-5- (trifluoromethyl)- 1H- pyrazol-3- yl]ureaD D A A A C*

Ex 209 1-(3-tert- butyl-1- methyl-1H- pyrazol-5- yl)-3-(3-(6-methoxy-7-(2- methoxyethoxy) quinazolin- 4- yloxy)phenyl) urea C D B D DC*

Ex 210 1-(3-tert- butyl-1- phenyl-1H- pyrazol-5- yl)-3-(3-(6- methoxy-7-(2- methoxyethoxy) quinazolin- 4- yloxy)phenyl) urea A ND D D D D*

Ex 211 1-(3-(1,1- difluoroethyl) isoxazol-5- yl)-3-(3-(6- methoxy-7- (2-methoxyethoxy) quinazolin- 4- yloxy)phenyl) urea D D B C B C*

Ex 212 1-[3-(2- ethoxypropan- 2-yl)-1- phenyl-1H- pyrazol-5-yl]-3-{3-[6- methoxy-7- (2- methoxyethoxy) quinazolin- 4- yloxy]phenyl}urea C D B D D C*

Ex 213 1-[5-(1,3- difluoro-2- methylpropan- 2- yl)isoxazol- 3-yl]-3-{3-[6-methoxy- 7-(2- methoxyethoxy) quinazolin- 4- yloxy]phenyl} urea A A AB A D*

Ex 214 1-(3- cyclopropyl- isoxazol-5- yl)-3-(3-(6- methoxy-7- (2-methoxyethoxy) quinazolin- 4- yloxy)phenyl) urea D D A A A C*

Ex 215 1-(3- isopropyl- isoxazol-5-yl)- 3-(3-(6- methoxy-7- (2-methoxyethoxy) quinazolin- 4- yloxy)phenyl) urea C D A B B C*

Ex 216 1-(3-(6- methoxy-7- (2- methoxyethoxy) quinazolin- 4-yloxy)phenyl)- 3-(3- (tetrahydro- 2H-pyran-4- yl)isoxazol- 5-yl)urea D DB D D B*

Ex 217 1-(5-(1- methoxy-2- methylpropan- 2- yl)isoxazol- 3-yl)-3-(3-(6-methoxy- 7-(2- methoxyethoxy) quinazolin- 4- yloxy)phenyl) urea B D AB B C*

Ex 218 1-(3-(2- fluoropropan- 2- yl)isoxazol- 5-yl)-3-(3- (6-methoxy-7-(2- methoxyethoxy) quinazolin- 4- yloxy)phenyl) urea B D A B A C*

Ex 219 1-(5- cyclopentyl- isoxazol-3-yl)- 3-(3-(6- methoxy-7- (2-methoxyethoxy) quinazolin- 4- yloxy)phenyl) urea A B A A A C*

Ex 220 1-{3-[6- methoxy-7- (2- methoxyethoxy) quinazolin- 4-yloxy]phenyl}- 3-[1- methyl-3- (trifluoromethyl)- 1H- pyrazol-5- yl]ureaC D A A A C*

Ex 221 1-{3-[6- methoxy-7- (2- methoxyethoxy) quinazolin- 4-yloxy]phenyl}- 3-[1- phenyl-3- (trifluoromethyl)- 1H- pyrazol-5- yl]ureaB C B D D C*

Ex 222 1-(3-fluoro- 4- (trifluoromethyl) phenyl)- 3-(3-(6- methoxy-7-(2- methoxyethoxy) quinazolin- 4- yloxy)phenyl) urea D D B C B C*

Ex 223 1-(3- methoxy-4- (trifluoromethyl) phenyl)- 3-(3-(6- methoxy-7-(2- methoxyethoxy) quinazolin- 4- yloxy)phenyl urea D D B D C C*

Ex 224 ethyl 2-[3- tert-butyl-5- (3-{3-[6- methoxy-7- (2-methoxy-ethoxy) quinazolin-4- yloxy] phenyl} ureido)- 1H-pyrazol- 1-yl]acetatehydrochloride D D D D D A*

Ex 225 1-{3-[6- methoxy-7- (2- methoxyethoxy) quinazolin- 4-yloxy]phenyl}- 3-[1- phenyl-5- (trifluoromethyl)- 1H- pyrazol-3- yl]ureaC D B D D C*

Ex 226 1-[1-(4- fluorophenyl)- 3- (trifluoromethyl)- 1H- pyrazol-5-yl]-3-{3-[6- methoxy-7- (2- methoxyethoxy) quinazolin- 4- yloxy]phenyl}urea B D C D D C*

Ex 227 1-{3-[6- methoxy-7- (2- methoxyethoxy) quinazolin- 4-yloxy]phenyl}- 3-[1-p- tolyl-3- (trifluoromethyl)- 1H- pyrazol-5-yl]urea B B C D D C*

Ex 228 1-[3-(1,3- difluoro-2- methylpropan- 2-yl)-1- phenyl-1H-pyrazol-5- yl]-3-{3-[6- methoxy-7- (2- methoxyethoxy) quinazolin- 4-yloxy]phenyl} urea A D C D D D*

Ex 229 1-(3-(6- methoxy-7- (2- methoxyethoxy) quinazolin-4-yloxy)phenyl)- 3-(3- (trifluoromethyl) isoxazol- 5-yl)urea D D A B A C*

Ex 230 1-[5-(1,3- difluoro-2- mcthylpropan- 2- yl)isoxazol- 3-yl]-3-{3-[6-methoxy- 7-(2- methoxyethoxy) quinazolin- 4- ylthio]phenyl} urea A BA C B C*

Ex 231 1-(3-fluoro- 4- (trifluoromethyl) phenyl)- 3-(3-(6- methoxy-7-(2- methoxyethoxy) quinazolin- 4- ylthio)phenyl) urea D D C D D B*

Ex 232 1-(5- isopropyl- isoxazol-3-yl)- 3-(3-(6- methoxy-7- (2-methoxyethoxy) quinazolin- 4- ylthio) phenyl)urea B D A A A C*

Ex 233 1-(3- methoxy-4- (trifluoromethyl) phenyl)- 3-(3-(6- methoxy-7-(2- methoxyethoxy) quinazolin- 4- ylthio)phenyl) urea D D C D D C*

Ex 234 1-(3-(2- fluoropropan- 2- yl)isoxazol- 5-yl)-3-(3- (6-methoxy-7-(2- methoxyethoxy) quinazolin- 4- ylthio)phenyl) urea A D A B B C*

Ex 235 1-(5- cyclopentyl- isoxazol-3- yl)-3-(3-(6- methoxy-7- (2-methoxyethoxy) quinazolin- 4- ylthio)phenyl) urea B D A B A C*

Ex 236 1-(3-tert- butyl-1- phenyl-1H- pyrazol-5- yl)-3-(3-(6- methoxy-7-(2- methoxyethoxy) quinazolin- 4- ylthio)phenyl) urea A ND D D D D*

Ex 237 ethyl 2-[3- tert-butyl-5- (3-{3-[6- methoxy-7- (2- methoxyethoxy)quinazolin- 4- ylthio]phenyl} ureido)-1H- pyrazol-1- yl]acetate C D C DD C*

Ex 238 1-[3-(1,3- difluoro-2- methylpropan- 2-yl)-1- phenyl-1H-pyrazol-5- yl]-3-{3-[6- methoxy-7- (2- methoxyethoxy) quinazolin- 4-ylthio]phenyl} urea A D D D D D*

Ex 239 1-{3-[6- methoxy-7- (2- methoxyethoxy) quinazolin- 4-ylthio]phenyl}- 3-[1- methyl-3- (trifluoromethyl)- 1H- pyrazol-5-yl]urea B D A A A D*

Ex 240 1-{3-[6- methoxy-7- (2- methoxyethoxy) quinazolin- 4-ylthio]phenyl}- 3-[1- methyl-3- (trifluoromethyl)- 1H- pyrazol-5-yl]urea B D A A A C*

Ex 241 1-[3-(2- ethoxypropan- 2-yl)-1- phenyl-1H- pyrazol-5-yl]-3-{3-[6- methoxy-7- (2- methoxyethoxy) quinazolin- 4- ylthio]phenyl}urea C D B D D C*

Ex 242 1-[1-(4- fluorophenyl)- 3- (trifluoromethyl)- 1H- pyrazol-5-yl]-3-{3-[6- methoxy-7- (2- methoxyethoxy) quinazolin- 4- ylthio]phenyl}urea C D D D D C*

Ex 243 1-{3-[6- methoxy-7- (2- methoxyethoxy) quinazolin- 4-ylthio]phenyl}- 3-[1-p- tolyl-3- (trifluoromethyl)- 1H- pyrazol-5-yl]urea B B D D D C*

Ex 244 1-{3-[6- methoxy-7- (2- methoxyethoxy) quinazolin- 4-ylthio]phenyl}- 3-[1- phenyl-5- (trifluoromethyl)- 1H- pyrazol-3-yl]urea D D D D D C*

Ex 245 1-(3-(2- fluoropropan- 2- yl)isoxazol- 5-yl)-3-(3- (7-methoxy-6-(4,4-dioxo- 3- thiomorpholino- propoxy) quinazolin-4- ylthio)phenyl)urea A D A A B C*

Ex 246 1-(4- methoxy-3- (trifluoromethyl) phenyl)- 3-(3-(7- methoxy-6-(3-(4,4- dioxothio- morpholino) propoxy) quinazolin-4- ylthio)phenyl)urea A C A B B C*

Ex 247 1-(3-(6,7- bis(2- Methoxyethoxy) quinazolin-4- ylthio)phenyl)-3-(3-tert- butylisoxazol- 5-yl)urea A D A B B C

Ex 248 1-(3-(2- fluoropropan- 2- yl)isoxazol- 5-yl)-3-(3- (6-methoxy-7-(2- morpholino- ethoxy) quinazolin-4- ylthio) phenyl)urea B D A B B C*

Ex 249 1-(4- methoxy-3- (trifluoromethyl) phenyl)- 3-(3-(6- methoxy-7-(2- morpholino- ethoxy) quinazolin-4- ylthio)phenyl) urea C D B C C C*

Ex 250 1-(4- methoxy-3- (trifluoromethyl) phenyl)- 3-(3-(6- methoxy-7-(2- morpholino- ethoxy) quinazolin-4- yloxy)phenyl) urea B D A A A C*

Ex 251 1-(3-(2- fluoropropan- 2- yl)isoxazol- 5-yl)-3-(3- (6-methoxy-7-(2- morpholino- ethoxy) quinazolin-4- yloxy)phenyl) urea B D A A B C*

Ex 252 1-(1-tert- butyl-1H- pyrazol-4- yl)-3-(3-(6,7- dimethoxy-quinazolin-4- yloxy)phenyl) urea D D A B B C

Ex 253 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6,7- dimethoxy-quinazolin-4- ylsulfinyl) phenyl)urea C D D D D C

Ex 254 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-(trifluoromethyl) isoxazol- 5-yl)urea D D A B A C*

Ex 255 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-(1-hydroxy-2- methylpropan- 2- yl)isoxazol- 5-yl)urea D D A B B C

Ex 256 1-(5-tert- butyl- isoxazol-3- yl)-3-(3-{7- [3-(1,1- dioxo-thiomorpholin- 4-yl)- propoxy]-6- methoxy- quinazolin-4- yloxy}-phenyl)-urea A A A A A D

Ex 257 1-(3-(2- fluoropropan- 2- yl)isoxazol- 5-yl)-3-(3- (7-hydroxy- 6-methoxy- quinazolin-4- yloxy)phenyl) urea B C A A A C

Ex 258 1-(3-(2- fluoropropan- 2- yl)isoxazol- 5-yl)-3-(3- (6-hydroxy- 7methoxy- quinazolin-4- yloxy)phenyl) urea A B A A A C

Ex 259 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(5-(1,1,1-trifluoro-2- methylpropan- 2- yl)isoxazol- 3-yl)urea A A A A A C

Ex 260 1-(3-(6- ethoxy-7- methoxy- quinazolin-4- yloxy)phenyl)-3-(5-(1,1,1- trifluoro-2- methylpropan- 2- yl)isoxazol- 3-yl)urea A A AA A C

Ex 261 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(5-(1,1,1-trifluoro-2- methylpropan- 2- yl)isoxazol- 3-yl)urea A D A B A ND

Ex 262 1-(3-(6- ethoxy-7- methoxy- quinazolin-4- ylthio)phenyl)-3-(5-(1,1,1- trifluoro-2- methylpropan- 2- yl)isoxazol- 3-yl)urea A D AA A C

Ex 263 1-(3-(7- hydroxy-6- methoxy- quinazolin-4- yloxy)phenyl)-3-(5-(1,1,1- trifluoro-2- methylpropan- 2- yl)isoxazol- 3-yl)urea A C AA A C

Ex 264 1-(3-(6- hydroxy-7- methoxy- quinazolin-4- yloxy)phenyl)-3-(5-(1,1,1- trifluoro-2- methylpropan- 2- yl)isoxazol- 3-yl)urea A A AA A C

Ex 265 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)-2- fluorophenyl)-3-(5-(1,1,1- trifluoro-2- methylpropan- 2- yl)isoxazol- 3-yl)urea A B AB A C

Ex 266 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)-4- fluorophenyl)-3-(5-(1,1,1- trifluoro-2- methylpropan- 2- yl)isoxazol- 3-yl)urea A ND AA A C

Ex 267 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-(1,1,1-trifluoro-2- methylpropan- 2- yl)isoxazol- 5-yl)urea A C A A A C

Ex 268 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(3-(1,1,1-trifluoro-2- methylpropan- 2- yl)isoxazol- 5-yl)urea A C A A A C

Ex 269 1-(5-(6,7- dimethoxy- quinazolin-4- yloxy)-2,4- difluorophenyl)-3-(3-(2- fluoropropan- 2- yl)isoxazol- 5-yl)urea A A A A A D

Ex 270 1-(5-tert- butylisoxazol- 3-yl)-3-(5- (6,7- dimethoxy-quinazolin-4- yloxy)-2,4- difluorophenyl) urea A A A A A D

Ex 271 1-(5-(6,7- dimethoxy- quinazolin-4- yloxy)-2,4- difluorophenyl)-3-(1- phenyl-3- (trifluoromethyl)- 1H- pyrazol-5- yl)urea A B B D D D

Ex 272 1-(3-tert- butyl-1-p- tolyl-1H- pyrazol-5- yl)-3-(5-(6,7-dimethoxy- quinazolin-4- yloxy)-2,4- difluorophenyl) urea A ND C D D D

Ex 273 1-(3-tert- butyl-1- phenyl-1H- pyrazol-5- yl)-3-(5-(6,7-dimethoxy- quinazolin-4- yloxy)-2,4- difluorophenyl) urea A ND C D D D

Ex 274 1-(3-tert- butyl-1-p- tolyl-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND B D D D

Ex 275 1-(3-tert- Butyl-1-p- tolyl-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- ylthio)phenyl) urea A ND B D D D

Ex 276 1-(3-tert- butyl-1-p- tolyl-1H- pyrazol-5- yl)-3-(3-(6-methoxy-7- (2- methoxyethoxy) quinazolin- 4- yloxy)phenyl) urea A ND A DD D

Ex 277 1-(3-tert- Butyl-1-p- tolyl-1H- pyrazol-5- yl)-3-(3-(6-methoxy-7- (2- methoxyethoxy) quinazolin- 4- ylthio)phenyl) urea A ND BD D D

Ex 278 1-(3-(2- cyanopropan- 2- yl)phenyl)-3- (3-(6,7- dimethoxy-quinazolin-4- yloxy)phenyl) urea B C A A A C

Ex 279 1-(3-(2- cyanopropan- 2- yl)phenyl)-3- (3-(6,7- dimethoxy-quinazolin-4- ylthio)phenyl) urea B D A A A C

Ex 280 1-(3-(2- cyanopropan- 2- yl)phenyl)-3- (3-(6- methoxy-7- (2-methoxyethoxy) quinazolin- 4- yloxy)phenyl) urea C D A A A ND

Ex 281 1-(3-(2- cyanopropan- 2- yl)phenyl)-3- (3-(6- methoxy-7- (2-methoxyethoxy) quinazolin- 4- ylthio)phenyl) urea B D A A A ND

Ex 282 1-(3-tert- butyl-1-(2,4- dimethylphenyl)- 1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND C D D C

Ex 283 1-(3-tert- butyl-1-(2,4- dimethylphenyl)- 1H- pyrazol-5-yl)-3-(3-(6- methoxy-7- (2- methoxyethoxy) quinazolin- 4- ylthio)phenyl)urea A D C D D C

Ex 284 1-(3-tert- butyl-1-(2,4- dimethylphenyl)- 1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl) urea A D D D D C

Ex 285 1-(3-tert- butyl-1-m- tolyl-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND B D D D

Ex 286 Preparation of 1-(3-tert- butyl-1-m- tolyl-1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl) urea A ND B D D D

Ex 287 1-(3-tert- butyl-1-m- tolyl-1H- pyrazol-5- yl)-3-(3-(6-methoxy-7- (2- methoxyethoxy) quinazolin- 4- ylthio)phenyl) urea A ND CD D D

Ex 288 1-(3-tert- butyl-1-p- tolyl-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- yloxy)-2- methylphenyl) urea A ND B D D C

Ex 289 1-(3-tert- butyl-1- phenyl-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- yloxy)-2- methylphenyl) urea A C A D C C

Ex 290 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (6,7- dimethoxy-quinazolin-4- yloxy)-2- methylphenyl) urea A B A A A C

Ex 291 1-(3-(6,7- Dimethoxy- quinazolin-4- yloxy)-2- methylphenyl)-3-(1- phenyl-3- (trifluoromethyl)- 1H- pyrazol-5- yl)urea C D A C B B

Ex 292 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)-2- methylphenyl)-3-(5-(2- fluoropropan- 2- yl)isoxazol- 3-yl)urea C D A A A C

Ex 293 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)-4- fluorophenyl)-3-(3-(2- fluoropropan- 2- yl)isoxazol- 5-yl)urea A B A A A C

Ex 294 1-(5-(1,3- difluoro-2- methylpropan- 2- yl)isoxazol- 3-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)-4- fluorophenyl) urea A ND A A A D

Ex 295 1-(3-tert- butyl-1- phenyl-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- yloxy)-2- fluorophenyl) urea C D A D C C

Ex 296 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)-2- fluorophenyl)-3-(3-(2- fluoropropan- 2- yl)isoxazol- 5-yl)urea D D A A A B

Ex 297 1-(5-(1,3- difluoro-2- methylpropan- 2- yl)isoxazol- 3-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)-2- fluorophenyl) urea B B A A A C

Ex 298 1-(3-tert- butyl-1-p- tolyl-1H- pyrazol-5- yl)-3-(2- chloro-5-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A A D D D D

Ex 299 1-(5-tert- butylisoxazol- 3-yl)-3-(2- chloro-5- (6,7- dimethoxy-quinazolin-4- yloxy)phenyl) urea A ND A B A C

Ex 300 1-(2-chloro- 5-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)-3-(1- phenyl-3- (trifluoromethyl)- 1H- pyrazol-5- yl)urea B D C D D C

Ex 301 1-(3-tert- butyl-1- phenyl-1H- pyrazol-5- yl)-3-(2- chloro-5-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A B D D D D

Ex 302 Preparation of 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)-3-(5-(2- methyl-1- morpholino- propan-2- yl)isoxazol- 3-yl)urea D D B DD B

Ex 303 1-(3-tert- butyl-1-(4- methylpyridin- 3-yl)-1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A A A C B D

Ex 304 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-(perfluoroethyl)- 1-phenyl- 1H-pyrazol- 5-yl)urea B A B D D C

Ex 305 1-(3-tert- butyl-1-(2- methylpyridin- 3-yl)-1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A A A C B D

Ex 306 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(1-phenyl-3- (1,1,1- trifluoro-2- methylpropan- 2-yl)-1H- pyrazol-5-yl)urea A ND B D D D

Ex 307 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(1-phenyl-3- (1,1,1- triiluoro-2- methylpropan- 2-yl)-1H- pyrazol-5-yl)urea A ND B D D D

Ex 308 1-(3-(2- cyanopropan- 2-yl)-1- phenyl-1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A B A B B D

Ex 309 1-(3-(2- cyanopropan- 2-yl)-1- phenyl-1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl) urea A ND A C C C

Ex 310 1-(5-tert- butylisoxazol- 3-yl)-3-(3- (2-chloro- 6,7- dimethoxy-quinazolin-4- yloxy)phenyl) urea D D C D C A

Ex 311 1-(3-(1,1- difluoroethyl)- 1-(pyridin- 3-yl)-1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea B B A A A C

Ex 312 1-(3-tert- butyl-1-(6- methylpyridin- 3-yl)-1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A A A C B D

Ex 313 Preparation of 1-(3-tert- butyl-1-(2- oxo-1,2- dihydropyridin-4-yl)-1H- pyrazol-5- yl)-3-(3-(6,7- dimethoxy- quinazolin-4-yloxy)phenyl) urea B C A B B D

Ex 314 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(1-(5-fluoropyridin- 3-yl)-3- isopropyl- 1H-pyrazol- 5-yl)urea B A A C B D

Ex 315 1-(3-(1,1- difluoroethyl)- 1-(4- methoxyphenyl)- 1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A A A D C D

Ex 316 1-(3-(1,1- difluoroethyl)- 1-(5- fluoropyridin- 3-yl)-1H-pyrazol-5- yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea BC A B A C

Ex 317 1-(3-tert- butyl-1-(6- oxo-1,6- dihydropyridin- 3-yl)-1H-pyrazol-5- yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea DD A D C D

Ex 318 1-(3-(1,1- difluoroethyl)- 1-phenyl- 1H-pyrazol- 5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A A A B B C

Ex 319 Preparation of 1-(3-(1,1- difluoroethyl)- 1-phenyl- 1H-pyrazol-5-yl)-3-(3- (6,7- dimethoxy- quinazolin-4- ylthio)phenyl) urea A A A C BC

Ex 320 1-(3-tert- butyl-1-(2- methylpyridin- 4-yl)-1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND A D D D

Ex 321 1-(3-tert- butyl-1- ethyl-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- ylthio)phenyl) urea B C A B A C

Ex 322 1-(3-tert- butyl-1- (pyridin-3- yl)-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND A B B D

Ex 323 1-(3-tert- butyl-1- (pyridin-3- yl)-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- ylthio)phenyl) urea A B A C C D

Ex 324 Preparation of 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)-3-(3- isopropyl-1- phenyl-1H- pyrazol-5- yl)urea A A A B B D

Ex 325 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(3-isopropyl-1- phenyl-1H- pyrazol-5- yl)urea A A A B B C

Ex 326 Preparation of 1-(3-tert- butyl-1-(5- fluoropyridin- 3-yl)-1H-pyrazol-5- yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea AND A C C D

Ex 327 1-(3-tert- butyl-1-(5- fluoropyridin- 3-yl)-1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl) urea A ND A C C D

Ex 328 1-(3-tert- butyl-1-(4- cyanophenyl)- 1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND A B B D

Ex 329 Preparation of 1-(3-tert- butyl-1-(4- cyanophenyl)- 1H-pyrazol-5- yl)-3-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl) urea AND B B C D

Ex 330 1-(3-tert- butyl-1- cyclohexyl- 1H- pyrazol- 5-yl)-3-(3- (6,7-dimethoxy- quinazolin-4- yloxy)phenyl) urea D D A D D C

Ex 331 1-(3-tert- butyl-1- cyclohexyl- 1H-pyrazol- 5-yl)-3-(3- (6,7-dimethoxy- quinazolin-4- ylthio)phenyl) urea A D B C C B

Ex 332 1-(3- tert-butyl-1- isobutyl-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- yloxy)phenyl) urea C D A B B C

Ex 333 1-(3-tert- butyl-1- isobutyl-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- ylthio)phenyl) urea C ND A B B C

Ex 334 1-(3-tert- butyl-1- isopropyl- 1H-pyrazol- 5-yl)-3-(3- (6,7-dimethoxy- quinazolin-4- yloxy)phenyl) urea C C A B B C

Ex 335 1-(3-tert- butyl-1- isopropyl- 1H-pyrazol- 5-yl)-3-(3- (6,7-dimethoxy- quinazolin-4- ylthio)phenyl) urea B D A B B C

Ex 336 1-(3-tert- butyl-1- (pyridin-4- yl)-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND A C C D

Ex 337 1-(3-tert- butyl-1- (pyridin-4- yl)-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- ylthio)phenyl) urea A ND A C C D

Ex 338 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(1-m-tolyl-3- (trifluoromethyl)- 1H- pyrazol-5- yl)urea A A A C B C

Ex 339 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(1-m-tolyl-3- (trifluoromethyl)- 1H- pyrazol-5- yl)urea A ND B D C C

Ex 340 1-(3-tert- butyl-1-(2- chlorophenyl)- 1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND B D D D

Ex 341 1-(3-tert- butyl-1-(2- chlorophenyl)- 1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl) urea A ND B D D C

Ex 342 1-(3-tert- butyl-1-o- tolyl-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND B D D D

Ex 343 1-(3-tert- butyl-1-o- tolyl-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- ylthio)phenyl) urea A ND B D D C

Ex 344 1-(3-tert- Butyl-1- (pyridin-2- yl)-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- yloxy)phenyl) urea C ND C D D C

Ex 345 1-(3-tert- butyl-1- (pyridin-2- yl)-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- ylthio)phenyl) urea C D D D D B

Ex 346 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(1-p-tolyl-3-(1- (trifluoromethyl) cyclopropyl)- 1H- pyrazol-5- yl)urea A NDA D D D

Ex 347 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(1-p-tolyl-3-(1- (trifluoromethyl) cyclopropyl)- 1H- pyrazol-5- yl)urea A NDB D D D

Ex 348 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-isopropyl-1- (4- methoxyphenyl)- 1H- pyrazol-5- yl)urea A A A D C D

Ex 349 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(3-isopropyl-1-(4- methoxyphenyl)- 1H- pyrazol-5- yl)urea A A A D C C

Ex 350 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-isopropyl-1- (pyridin-3- yl)-1H- pyrazol-5- yl)urea B B A A A D

Ex 351 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(3-isopropyl-1- (pyridin-3- yl)-1H- pyrazol-5- yl)urea A B A C A C

Ex 352 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(3-ethyl-1-phenyl- 1H-pyrazol- 5-yl)urea C B A A A C

Ex 353 1-(3- cyclopropyl- 1-phenyl- 1H-pyrazol- 5-yl)-3-(3- (6,7-dimethoxy- quinazolin-4- yloxy)phenyl) urea B B A B A C

Ex 354 1-(3- cyclopropyl- 1-phenyl- 1H-pyrazol- 5-yl)-3-(3- (6,7-dimethoxy- quinazolin-4- ylthio)phenyl) urea B B A A A C

Ex 355 Preparation of 1-(3- cyclobutyl-1- phenyl-1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A A A C C C

Ex 356 1-(3- cyclobutyl-1- phenyl-1H- pyrazol-5- yl)-3-(3-(6,7-dimethoxy- quinazolin-4- ylthio)phenyl) urea B A A D C C

Ex 357 1-(1-benzyl- 3-tert-butyl- 1H-pyrazol- 5-yl)-3-(3- (6,7-dimethoxy- quinazolin-4- yloxy)phenyl) urea B D A C D C

Ex 358 1-(1-benzyl- 3-tert-butyl- 1H-pyrazol- 5-yl)-3-(3- (6,7-dimethoxy- quinazolin-4- ylthio)phenyl) urea B ND A D D C

Ex 359 1-(3-tert- butyl-1-(3- fluorophenyl)- 1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND A D D D

Ex 360 1-(3-tert- butyl-1-(3- fluorophenyl)- 1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl) urea A ND B D D D

Ex 361 1-(3-tert- butyl-1-(4- methoxyphenyl)- 1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A D A B C C

Ex 362 Preparation of 1-(3-tert- butyl-1-(4- methoxyphenyl)- 1H-pyrazol-5- yl)-3-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl) urea AND C D D D

Ex 363 1-(3-tert- butyl-1-(3- chlorophenyl)- 1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND A B D D

Ex 364 1-(3-tert- butyl-1-(3- chlorophenyl)- 1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl) urea A ND A C D D

Ex 365 1-(3-tert- butyl-1-(4- chlorophenyl)- 1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND B D D D

Ex 366 1-(3-tert- butyl-1-(4- chlorophenyl)- 1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl) urea A ND B D D D

Ex 367 1-(5-tert- butylisoxazol- 3-yl)-3-(5- (6,7- dimethoxy-quinazolin-4- yloxy)-2- fluorophenyl) urea A B A A A D

Ex 368 1-(3-tert- butyl-1- phenyl-1H- pyrazol-5- yl)-3-(5-(6,7-dimethoxy- quinazolin-4- yloxy)-2- fluorophenyl) urea A ND C D D D

Ex 369 1-(3-tert- butyl-1-(4- tert- butylphenyl)- 1H-pyrazol-5-yl)-3-(3- (6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A D A C DC

Ex 370 1-(3-tert- butyl-1-(4- tert- butylphenyl)- 1H-pyrazol-5-yl)-3-(3- (6,7- dimethoxy- quinazolin-4- ylthio)phenyl) urea A ND A DD D

Ex 371 1-(3-tert- butyl-1-(2- fluorophenyl)- 1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl) urea A ND B D D D

Ex 372 1-(3-tert- butyl-1-(2- fluorophenyl)- 1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND A C C D

Ex 373 1-(3-tert- butyl-1-(4- (trifluoromethyl) phenyl)- 1H-pyrazol-5-yl)-3-(3- (6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND C D DC

Ex 374 1-(3-tert- butyl-1-(4- (trifluoromethyl) phenyl)- 1H-pyrazol-5-yl)-3- (3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl) urea A ND B DD C

Ex 375 1-(3-tert- butyl-1-(2- (trifluoromethyl) phenyl)- 1H-pyrazol-5-yl)-3-(3- (6,7- dimethoxy- quinazolin-4- ylthio)phenyl) urea A ND C DD C

Ex 376 1-(3-tert- butyl-1-(2- (trifluoromethyl) phenyl)- 1H-pyrazol-5-yl)-3-(3- (6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND C D DD

Ex 377 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl)- 3-(5-(1-(trifluoromethyl) cyclopropyl) isoxazol- 3-yl)urea A A A A A C

Ex 378 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(5-(1-(trifluoromethyl) cyclopropyl) isoxazol- 3-yl)urea B A A A A C

Ex 379 1-(3-tert- butyl-1-(3- (trifluoromethyl) phenyl)- 1H-pyrazol-5-yl)-3-(3- (6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND B D DD

Ex 380 1-(3-tert- butyl-1-(3- (trifluoromethyl) phenyl)- 1H-pyrazol-5-yl)-3-(3- (6,7- dimethoxy- quinazolin-4- ylthio)phenyl) urea A ND B DD C

Ex 381 1-(3-(2- cyanopropan- 2- yl)isoxazol- 5-yl)-3-(3- (6,7-dimethoxy- quinazolin-4- ylthio)phenyl) urea A ND A A A C

Ex 382 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(3-(trifluoromethyl) isoxazol- 5-yl)urea D D A A A C

Ex 383 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(1-phenyl-3-(1- (trifluoromethyl) cyclopropyl)- 1H- pyrazol-5- yl)urea A NDB D D C

Example 384 Preparation of 1-(3-(7- ethoxy-6- methoxy- quinazolin-4-yloxy)phenyl)- 3-(1- phenyl-3- (trifluoromethyl)- 1H- pyrazol-5- yl)ureaC B A C B C

Ex 385 1-(3-(7- ethoxy-6- methoxy- quinazolin-4- yloxy)phenyl)- 3-(3-(2-fluoropropan- 2- yl)isoxazol- 5-yl)urea B B A A A C

Ex 386 1-(5-(1,3- difluoro-2- methylpropan- 2- yl)isoxazol- 3-yl)-3-(3-(7-ethoxy-6- methoxy- quinazolin-4- yloxy)phenyl) urea A A A A A C

Ex 387 1-(3-tert- butyl-1- phenyl-1H- pyrazol-5- yl)-3-(3-(7- ethoxy-6-methoxy- quinazolin-4- yloxy)phenyl) urea A ND A C C D

Example 388 Preparation of 1-(5-(1,3- difluoro-2- methylpropan- 2-yl)isoxazol- 3-yl)-3-(3- (7-ethoxy-6- methoxy- quinazolin-4-ylthio)phenyl) urea B B A A A C

Ex 389 1-(3-(7- ethoxy-6- methoxy- quinazolin-4- ylthio)phenyl)-3-(3-(2- fluoropropan- 2- yl)isoxazol- 5-yl)urea C B A A A C

Ex 390 1-(3-tert- butyl-1- phenyl-1H- pyrazol-5- yl)-3-(3-(6- ethoxy-7-methoxy- quinazolin-4- yloxy)phenyl) urea A ND A B C D

Ex 391 1-(3-(6- ethoxy-7- methoxy- quinazolin-4- yloxy)phenyl)- 3-(1-phenyl-3- (trifluoromethyl)- 1H- pyrazol-5- yl)urea A A A B B C

Ex 392 1-(3-(6- ethoxy-7- methoxy- quinazolin-4- yloxy)phenyl)- 3-(3-(2-fluoropropan- 2- yl)isoxazol- 5-yl)urea A A A A A C

Ex 393 1-(5-(1,3- difluoro-2- mcthylpropan- 2- yl)isoxazol- 3-yl)-3-(3-(6-ethoxy-7- methoxy- quinazolin-4- yloxy)phenyl) urea A A A A A C

Ex 394 1-(3-(6- ethoxy-7- methoxy- quinazolin-4- ylthio)phenyl)-3-(3-(2- fluoropropan- 2- yl)isoxazol- 5-yl)urea A B A A A C

Ex 395 1-(5-(1,3- difluoro-2- methylpropan- 2- yl)isoxazol- 3-yl)-3-(3-(6-ethoxy-7- methoxy- quinazolin-4- ylthio)phenyl) urea A A A A A C

Ex 396 (1-(3-(6- methoxy-7- (2- morpholino- ethoxy) quinazolin-4-yloxy)phenyl)- 3-(1- phenyl-3- (trifluoromethyl)- 1H- pyrazol-5- yl)ureaC C A C C C

Ex 397 1-(3-(6,7- dimethoxy- quinazolin-4- yloxy)-4- fluorophenyl)-3-(1- phenyl-3- (trifluoromethyl)- 1H- pyrazol-5- yl)urea A B A D C C

Ex 398 1-(3-tert- butyl-1-(4- methoxyphenyl)- 1H- pyrazol-5-yl)-3-(3-(6,7- dimethoxy- quinazolin-4- yloxy)phenyl) urea A ND A C C D

Ex 399 1-(3-(6,7- dimethoxy- quinazolin-4- ylthio)phenyl)- 3-(3-ethyl-1-phenyl- 1H-pyrazol- 5-yl)urea B B A A A C pMEK IC₅₀ and A375 ViabilityEC₅₀: A ≦ 250, 250 < B ≦ 500, 500 < C ≦ 1000, D > 1000, BRAF V600E Kd,BRAF WT Kd and RAF1 Kd: A ≦ 250, 250 < B ≦ 500, 500 < C ≦ 1000, D >1000, S35: A ≦ 0.10, 0.10 < B ≦ 0.20, 0.20 < C ≦ 0.40, D > 0.40(Asterisk indicates an S35 score calculated using a panel of 321distinct kinases, no asterisk indicates an S35 score calculated using apanel of 290 distinct kinases); and ND = no data.

Also provided herein are isotopically enriched analogs of the compoundsprovided herein. Isotopic enrichment (for example, deuteration) ofpharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics(“PD”), and toxicity profiles, has been demonstrated previously withsome classes of drugs. See, for example, Lijinsky et. al., Food Cosmet.Toxicol., 20: 393 (1982); Lijinsky et. al., J. Nat. Cancer Inst., 69:1127 (1982); Mangold et. al., Mutation Res. 308: 33 (1994); Gordon et.al., Drug Metab. Dispos., 15: 589 (1987); Zello et. al., Metabolism, 43:487 (1994); Gately et. al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem.Biol. Interact. 117: 191 (1999).

Isotopic enrichment of a drug can be used, for example, to (1) reduce oreliminate unwanted metabolites, (2) increase the half-life of the parentdrug, (3) decrease the number of doses needed to achieve a desiredeffect, (4) decrease the amount of a dose necessary to achieve a desiredeffect, (5) increase the formation of active metabolites, if any areformed, and/or (6) decrease the production of deleterious metabolites inspecific tissues and/or create a more effective drug and/or a safer drugfor combination therapy, whether the combination therapy is intentionalor not.

Replacement of an atom for one of its isotopes often will result in achange in the reaction rate of a chemical reaction. This phenomenon isknown as the Kinetic Isotope Effect (“KIE”). For example, if a C—H bondis broken during a rate-determining step in a chemical reaction (i.e.the step with the highest transition state energy), substitution of adeuterium for that hydrogen will cause a decrease in the reaction rateand the process will slow down. This phenomenon is known as theDeuterium Kinetic Isotope Effect (“DKIE”). (See, e.g, Foster et al.,Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J.Physiol. Pharmacol., vol. 77, pp. 79-88 (1999)).

Tritium (“T”) is a radioactive isotope of hydrogen, used in research,fusion reactors, neutron generators and radiopharmaceuticals. Tritium isa hydrogen atom that has 2 neutrons in the nucleus and has an atomicweight close to 3. It occurs naturally in the environment in very lowconcentrations, most commonly found as T₂O. Tritium decays slowly(half-life=12.3 years) and emits a low energy beta particle that cannotpenetrate the outer layer of human skin. Internal exposure is the mainhazard associated with this isotope, yet it must be ingested in largeamounts to pose a significant health risk. As compared with deuterium, alesser amount of tritium must be consumed before it reaches a hazardouslevel. Substitution of tritium (“T”) for hydrogen results in yet astronger bond than deuterium and gives numerically larger isotopeeffects. Similarly, substitution of isotopes for other elements,including, but not limited to, ¹³C or ¹⁴C for carbon, ³³S, ³⁴S, or ³⁶Sfor sulfur, ¹⁵N for nitrogen, and ¹⁷O or ¹⁸O for oxygen, will provide asimilar kinetic isotope effects.

In another embodiment, provided herein are methods of using thedisclosed compounds and compositions, or pharmaceutically acceptablesalts, solvates, or hydrates thereof, for the local or systemictreatment or prophylaxis of human and veterinary diseases, disorders andconditions modulated or otherwise affected mediated via RAF kinase,including BRAF kinase, activity.

C. Formulation of Pharmaceutical Compositions

Provided herein are pharmaceutical compositions comprising a compoundprovided herein, e.g., a compound of Formula I, as an active ingredient,or a pharmaceutically acceptable salt, solvate or hydrate thereof; incombination with a pharmaceutically acceptable vehicle, carrier,diluent, or excipient, or a mixture thereof.

The compound provided herein may be administered alone, or incombination with one or more other compounds provided herein. Thepharmaceutical compositions that comprise a compound provided herein,e.g., a compound of Formula I, can be formulated in various dosage formsfor oral, parenteral, and topical administration. The pharmaceuticalcompositions can also be formulated as modified release dosage forms,including delayed-, extended-, prolonged-, sustained-, pulsatile-,controlled-, accelerated- and fast-, targeted-, programmed-release, andgastric retention dosage forms. These dosage forms can be preparedaccording to conventional methods and techniques known to those skilledin the art (see, Remington: The Science and Practice of Pharmacy, supra;Modified-Release Drug Deliver Technology, Rathbone et al., Eds., Drugsand the Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y.,2003; Vol. 126).

In one embodiment, the pharmaceutical compositions are provided in adosage form for oral administration, which comprise a compound providedherein, e.g., a compound of Formula I, or a pharmaceutically acceptablesalt, solvate or hydrate thereof; and one or more pharmaceuticallyacceptable excipients or carriers.

In another embodiment, the pharmaceutical compositions are provided in adosage form for parenteral administration, which comprise a compoundprovided herein, e.g., a compound of Formula I, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof; and one or morepharmaceutically acceptable excipients or carriers.

In yet another embodiment, the pharmaceutical compositions are providedin a dosage form for topical administration, which comprise a compoundprovided herein, e.g., a compound of Formula I, or a pharmaceuticallyacceptable salt, solvateor hydrate thereof; and one or morepharmaceutically acceptable excipients or carriers.

The pharmaceutical compositions provided herein can be provided in aunit-dosage form or multiple-dosage form. A unit-dosage form, as usedherein, refers to physically discrete a unit suitable for administrationto a human and animal subject, and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of an activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of a unit-dosage form include an ampoule, syringe, andindividually packaged tablet and capsule. A unit-dosage form may beadministered in fractions or multiples thereof. A multiple-dosage formis a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dosage form. Examples ofa multiple-dosage form include a vial, bottle of tablets or capsules, orbottle of pints or gallons. The pharmaceutical compositions providedherein can be administered at once, or multiple times at intervals oftime. It is understood that the precise dosage and duration of treatmentmay vary with the age, weight, and condition of the patient beingtreated, and may be determined empirically using known testing protocolsor by extrapolation from in vivo or in vitro test or diagnostic data. Itis further understood that for any particular individual, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the formulations.

In one embodiment, the therapeutically effective dose is from about 0.1mg to about 2,000 mg per day of a compound provided herein. Thepharmaceutical compositions therefore should provide a dosage of fromabout 0.1 mg to about 2000 mg of the compound. In certain embodiments,pharmaceutical dosage unit forms are prepared to provide from about 1 mgto about 2000 mg, from about 10 mg to about 1000 mg, from about 20 mg toabout 500 mg or from about 25 mg to about 250 mg of the essential activeingredient or a combination of essential ingredients per dosage unitform. In certain embodiments, the pharmaceutical dosage unit forms areprepared to provide about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg,500 mg, 1000 mg or 2000 mg of the essential active ingredient.

Oral Administration

The pharmaceutical compositions provided herein can be provided insolid, semisolid, or liquid dosage forms for oral administration. Asused herein, oral administration also includes buccal, lingual, andsublingual administration. Suitable oral dosage forms include, but arenot limited to, tablets, fastmelts, chewable tablets, capsules, pills,troches, lozenges, pastilles, cachets, pellets, medicated chewing gum,bulk powders, effervescent or non-effervescent powders or granules,solutions, emulsions, suspensions, wafers, sprinkles, elixirs, andsyrups. In addition to the active ingredient(s), the pharmaceuticalcompositions can contain one or more pharmaceutically acceptablecarriers or excipients, including, but not limited to, binders, fillers,diluents, disintegrants, wetting agents, lubricants, glidants, coloringagents, dye-migration inhibitors, sweetening agents, and flavoringagents.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The binder or filler may be present fromabout 50 to about 99% by weight in the pharmaceutical compositionsprovided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of a disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The pharmaceutical compositions provided herein may containfrom about 0.5 to about 15% or from about 1 to about 5% by weight of adisintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (CabotCo. of Boston, Mass.), and asbestos-free talc. Coloring agents includeany of the approved, certified, water soluble FD&C dyes, and waterinsoluble FD&C dyes suspended on alumina hydrate, and color lakes andmixtures thereof A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Flavoring agents include natural flavorsextracted from plants, such as fruits, and synthetic blends of compoundswhich produce a pleasant taste sensation, such as peppermint and methylsalicylate. Sweetening agents include sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include gelatin, acacia,tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitanmonooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN®80), and triethanolamine oleate. Suspending and dispersing agentsinclude sodium carboxymethylcellulose, pectin, tragacanth, Veegum,acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Preservatives include glycerin, methyl andpropylparaben, benzoic add, sodium benzoate and alcohol. Wetting agentsinclude propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate, and polyoxyethylene lauryl ether. Solvents includeglycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueousliquids utilized in emulsions include mineral oil and cottonseed oil.Organic acids include citric and tartaric acid. Sources of carbondioxide include sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

The pharmaceutical compositions provided herein can be provided ascompressed tablets, tablet triturates, chewable lozenges, rapidlydissolving tablets, multiple compressed tablets, or enteric-coatingtablets, sugar-coated, or film-coated tablets. Enteric-coated tabletsare compressed tablets coated with substances that resist the action ofstomach acid but dissolve or disintegrate in the intestine, thusprotecting the active ingredients from the acidic environment of thestomach. Enteric-coatings include, but are not limited to, fatty acids,fats, phenyl salicylate, waxes, shellac, ammoniated shellac, andcellulose acetate phthalates. Sugar-coated tablets are compressedtablets surrounded by a sugar coating, which may be beneficial incovering up objectionable tastes or odors and in protecting the tabletsfrom oxidation. Film-coated tablets are compressed tablets that arecovered with a thin layer or film of a water-soluble material. Filmcoatings include, but are not limited to, hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000, and cellulose acetatephthalate. Film coating imparts the same general characteristics assugar coating. Multiple compressed tablets are compressed tablets madeby more than one compression cycle, including layered tablets, andpress-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein can be provided as softor hard capsules, which can be made from gelatin, methylcellulose,starch, or calcium alginate. The hard gelatin capsule, also known as thedry-filled capsule (DFC), consists of two sections, one slipping overthe other, thus completely enclosing the active ingredient. The softelastic capsule (SEC) is a soft, globular shell, such as a gelatinshell, which is plasticized by the addition of glycerin, sorbitol, or asimilar polyol. The soft gelatin shells may contain a preservative toprevent the growth of microorganisms. Suitable preservatives are thoseas described herein, including methyl- and propyl-parabens, and sorbicacid. The liquid, semisolid, and solid dosage forms provided herein maybe encapsulated in a capsule. Suitable liquid and semisolid dosage formsinclude solutions and suspensions in propylene carbonate, vegetableoils, or triglycerides. Capsules containing such solutions can beprepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and4,410,545. The capsules may also be coated as known by those of skill inthe art in order to modify or sustain dissolution of the activeingredient.

The pharmaceutical compositions provided herein can be provided inliquid and semisolid dosage forms, including emulsions, solutions,suspensions, elixirs, and syrups. An emulsion is a two-phase system, inwhich one liquid is dispersed in the form of small globules throughoutanother liquid, which can be oil-in-water or water-in-oil. Emulsions mayinclude a pharmaceutically acceptable non-aqueous liquid or solvent,emulsifying agent, and preservative. Suspensions may include apharmaceutically acceptable suspending agent and preservative. Aqueousalcoholic solutions may include a pharmaceutically acceptable acetal,such as a di(lower alkyl)acetal of a lower alkyl aldehyde, e.g.,acetaldehyde diethyl acetal; and a water-miscible solvent having one ormore hydroxyl groups, such as propylene glycol and ethanol. Elixirs areclear, sweetened, and hydroalcoholic solutions. Syrups are concentratedaqueous solutions of a sugar, for example, sucrose, and may also containa preservative. For a liquid dosage form, for example, a solution in apolyethylene glycol may be diluted with a sufficient quantity of apharmaceutically acceptable liquid carrier, e.g., water, to be measuredconveniently for administration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations can further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationcan be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein can be provided asnon-effervescent or effervescent, granules and powders, to bereconstituted into a liquid dosage form. Pharmaceutically acceptablecarriers and excipients used in the non-effervescent granules or powdersmay include diluents, sweeteners, and wetting agents. Pharmaceuticallyacceptable carriers and excipients used in the effervescent granules orpowders may include organic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein can be formulated asimmediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical compositions provided herein can be co-formulatedwith other active ingredients which do not impair the desiredtherapeutic action, or with substances that supplement the desiredaction.

Parenteral Administration

The pharmaceutical compositions provided herein can be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

The pharmaceutical compositions provided herein can be formulated in anydosage forms that are suitable for parenteral administration, includingsolutions, suspensions, emulsions, micelles, liposomes, microspheres,nanosystems, and solid forms suitable for solutions or suspensions inliquid prior to injection. Such dosage forms can be prepared accordingto conventional methods known to those skilled in the art ofpharmaceutical science (see, Remington: The Science and Practice ofPharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationcan include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Non-aqueous vehicles include, but are not limited to, fixed oils ofvegetable origin, castor oil, corn oil, cottonseed oil, olive oil,peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Water-miscible vehiclesinclude, but are not limited to, ethanol, 1,3-butanediol, liquidpolyethylene glycol (e.g., polyethylene glycol 300 and polyethyleneglycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone,N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsinclude those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

The pharmaceutical compositions provided herein can be formulated forsingle or multiple dosage administration. The single dosage formulationsare packaged in an ampoule, a vial, or a syringe. The multiple dosageparenteral formulations must contain an antimicrobial agent atbacteriostatic or fungistatic concentrations. All parenteralformulations must be sterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions are provided asready-to-use sterile solutions. In another embodiment, thepharmaceutical compositions are provided as sterile dry solubleproducts, including lyophilized powders and hypodermic tablets, to bereconstituted with a vehicle prior to use. In yet another embodiment,the pharmaceutical compositions are provided as ready-to-use sterilesuspensions. In yet another embodiment, the pharmaceutical compositionsare provided as sterile dry insoluble products to be reconstituted witha vehicle prior to use. In still another embodiment, the pharmaceuticalcompositions are provided as ready-to-use sterile emulsions.

The pharmaceutical compositions provided herein can be formulated asimmediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical compositions can be formulated as a suspension,solid, semi-solid, or thixotropic liquid, for administration as animplanted depot. In one embodiment, the pharmaceutical compositionsprovided herein are dispersed in a solid inner matrix, which issurrounded by an outer polymeric membrane that is insoluble in bodyfluids but allows the active ingredient in the pharmaceuticalcompositions diffuse through.

Suitable inner matrixes include polymethylmethacrylate,polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethylene terephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinyl acetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers, such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinyl alcohol, and cross-linked partiallyhydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinyl chloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer.

Topical Administration

The pharmaceutical compositions provided herein can be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, includes (intra)dermal, conjunctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,urethral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein can be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, dermal patches. Thetopical formulation of the pharmaceutical compositions provided hereincan also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions can also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis, ormicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein can be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including lard, benzoinated lard,olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid (see, Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Cream vehiclesmay be water-washable, and contain an oil phase, an emulsifier, and anaqueous phase. The oil phase is also called the “internal” phase, whichis generally comprised of petrolatum and a fatty alcohol such as cetylor stearyl alcohol. The aqueous phase usually, although not necessarily,exceeds the oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation may be a nonionic, anionic, cationic,or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include crosslinked acrylicacid polymers, such as carbomers, carboxypolyalkylenes, CARBOPOL®;hydrophilic polymers, such as polyethylene oxides,polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol;cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, and methylcellulose; gums, such as tragacanth and xanthangum; sodium alginate; and gelatin. In order to prepare a uniform gel,dispersing agents such as alcohol or glycerin can be added, or thegelling agent can be dispersed by trituration, mechanical mixing, and/orstirring.

The pharmaceutical compositions provided herein can be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature, when formulated with the pharmaceuticalcompositions provided herein; and antioxidants as described herein,including bisulfite and sodium metabisulfite. Suitable vehicles include,but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,carbowax (polyoxyethylene glycol), spermaceti, paraffin, white andyellow wax, and appropriate mixtures of mono-, di- and triglycerides offatty acids, hydrogels, such as polyvinyl alcohol, hydroxyethylmethacrylate, polyacrylic acid; glycerinated gelatin. Combinations ofthe various vehicles may be used. Rectal and vaginal suppositories maybe prepared by the compressed method or molding. The typical weight of arectal and vaginal suppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein can be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical compositions provided herein can be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions can be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions canalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder can comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer can be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein, a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein can be micronized to asize suitable for delivery by inhalation, such as about 50 micrometersor less, or about 10 micrometers or less. Particles of such sizes can beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters and cartridges for use in an inhaler or insufflatorcan be formulated to contain a powder mix of the pharmaceuticalcompositions provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients or carriers include dextran,glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.The pharmaceutical compositions provided herein for inhaled/intranasaladministration can further comprise a suitable flavor, such as mentholand levomenthol, or sweeteners, such as saccharin or saccharin sodium.

The pharmaceutical compositions provided herein for topicaladministration can be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

Modified Release

The pharmaceutical compositions provided herein can be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include delayed-, extended-, prolonged-, sustained-, pulsatile-,controlled-, accelerated- and fast-, targeted-, programmed-release, andgastric retention dosage forms. The pharmaceutical compositions inmodified release dosage forms can be prepared using a variety ofmodified release devices and methods known to those skilled in the art,including, but not limited to, matrix controlled release devices,osmotic controlled release devices, multiparticulate controlled releasedevices, ion-exchange resins, enteric coatings, multilayered coatings,microspheres, liposomes, and combinations thereof. The release rate ofthe active ingredient(s) can also be modified by varying the particlesizes and polymorphorism of the active ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324;6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461;6,419,961; 6,589,548; 6,613,358; and 6,699,500.

1. Matrix Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using a matrix controlled release deviceknown to those skilled in the art (see, Takada et al in “Encyclopedia ofControlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).

In one embodiment, the pharmaceutical compositions provided herein in amodified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including synthetic polymers, and naturally occurring polymers andderivatives, such as polysaccharides and proteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; and cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acidesters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acidor methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.);poly(2-hydroxyethyl-methacrylate); polylactides; copolymers ofL-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolicacid copolymers; poly-D-(−)-3-hydroxybutyric acid; and other acrylicacid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate,(2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In further embodiments, the pharmaceutical compositions are formulatedwith a non-erodible matrix device. The active ingredient(s) is dissolvedor dispersed in an inert matrix and is released primarily by diffusionthrough the inert matrix once administered. Materials suitable for useas a non-erodible matrix device included, but are not limited to,insoluble plastics, such as polyethylene, polypropylene, polyisoprene,polyisobutylene, polybutadiene, polymethylmethacrylate,polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride,methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetatecopolymers, ethylene/propylene copolymers, ethylene/ethyl acrylatecopolymers, vinyl chloride copolymers with vinyl acetate, vinylidenechloride, ethylene and propylene, ionomer polyethylene terephthalate,butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethylene terephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, silicone carbonate copolymers, and;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate,and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients or carriers in the compositions.

The pharmaceutical compositions provided herein in a modified releasedosage form can be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using an osmotic controlled releasedevice, including one-chamber system, two-chamber system, asymmetricmembrane technology (AMT), and extruding core system (ECS). In general,such devices have at least two components: (a) the core which containsthe active ingredient(s); and (b) a semipermeable membrane with at leastone delivery port, which encapsulates the core. The semipermeablemembrane controls the influx of water to the core from an aqueousenvironment of use so as to cause drug release by extrusion through thedelivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels,”including, but not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol, organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates can be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MANNOGEM™EZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core can also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking Examples ofsuitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane can also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane can be formedpost-coating by mechanical or laser drilling. Delivery port(s) can alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports can be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosageform can further comprise additional conventional excipients or carriersas described herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J.Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMTcontrolled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated as a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates can be made by the processes known to those skilled inthe art, including wet- and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker:1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients or carriers as described herein can be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles can themselves constitute themultiparticulate device or can be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

4. Targeted Delivery

The pharmaceutical compositions provided herein can also be formulatedto be targeted to a particular tissue, receptor, or other area of thebody of the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, U.S. Pat. Nos. 6,316,652; 6,274,552; 6,271,359;6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082;6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252;5,840,674; 5,759,542; and 5,709,874.

D. Evaluation of the Activity of the Compounds

Standard physiological, pharmacological and biochemical procedures areavailable for testing the compounds to identify those that possessbiological activities that modulate the activity of BRAF kinases,including wild type and mutant BRAF kinases.

Such assays include, for example, biochemical assays such as bindingassays, radioactivity incorporation assays, as well as a variety of cellbased assays.

Exemplary cell based assay methodologies include measurement of MEKphosphorylation inhibition in the A375 human melanoma cell line,inhibition of cell proliferation in the A375 human melanoma cell line.

Cells useful in the assays include cells with wildtype or mutated forms.Suitable cells include those derived through cell culture from patientsamples as well as cells derived using routine molecular biologytechniques, e.g., retroviral transduction, transfection, mutagenesis,etc.

E. Methods of Use of the Compounds and Compositions

Also provided herein are methods of using the disclosed compounds andcompositions, or pharmaceutically acceptable salts, solvates, orhydrates thereof, for the treatment, prevention, or amelioration of adisease or disorder that is mediated or otherwise affected via RAFkinase, including BRAF kinase activity or one or more symptoms ofdiseases or disorders that are mediated or otherwise affected via RAFkinase, including BRAF kinase, activity. BRAF kinase can be wild typeand/or mutant form of BRAF kinase. In one embodiment, provided hereinare methods for treatment of diseases or disorders including withoutlimitation: cancers, including melanoma, papillary thyroid carcinoma,colorectal, ovarian, breast cancer, endometrial cancer, liver cancer,sarcoma, stomach cancer, Barret's adenocarcinoma, glioma (includingependymoma), lung cancer (including non small cell lung cancer), headand neck cancer, acute lymphoblastic leukemia and non-Hodgkin'slymphoma; and inflammatory diseases or disorders related to immunedysfunction, immunodeficiency, immunomodulation, autoimmune diseases,tissue transplant rejection, graft-versus-host disease, wound healing,kidney disease, multiple sclerosis, thyroiditis, type 1 diabetes,sarcoidosis, allergic rhinitis, inflammatory bowel disease includingCrohn's disease and ulcerative colitis (UC), systemic lupuserythematosis (SLE), arthritis, osteoarthritis, rheumatoid arthritis,osteoporosis, asthma and chronic obstructive pulmonary disease (COPD).

In one embodiment, provided herein are methods for treating cancersincluding blood borne and solid tumors.

F. Combination Therapy

Furthermore, it will be understood by those skilled in the art thatcompounds provided herein, including pharmaceutical compositions andformulations containing these compounds, can be used in a wide varietyof combination therapies to treat the conditions and diseases describedabove. Thus, also contemplated herein is the use of compounds andpharmaceutically acceptable salts provided herein in combination withother active pharmaceutical agents for the treatment of thedisease/conditions described herein.

In one embodiment, such additional pharmaceutical agents include withoutlimitation anti-cancer agents, including chemotherapeutic agents andanti-proliferative agents; anti-inflammatory agents and immunomodulatoryagents or immunosuppressive agents.

In certain embodiments, the anti-cancer agents include anti-metabolites(e.g., 5-fluoro-uracil, methotrexate, fludarabine and others),antimicrotubule agents (e.g., vinca alkaloids such as vincristine,vinblastine; taxanes such as paclitaxel and docetaxel), alkylatingagents (e.g., cyclophosphamide, melphalan, carmustine, nitrosoureas suchas bischloroethylnitrosurea and hydroxyurea), platinum agents (e.g.cisplatin, carboplatin, oxaliplatin, satraplatin and CI-973),anthracyclines (e.g., doxrubicin and daunorubicin), antitumorantibiotics (e.g., mitomycin, idarubicin, adriamycin and daunomycin),topoisomerase inhibitors (e.g., etoposide and camptothecins),anti-angiogenesis agents (e.g. Sutent®, sorafenib and Bevacizumab) orany other cytotoxic agents, (estramustine phosphate, prednimustine),hormones or hormone agonists, antagonists, partial agonists or partialantagonists, kinase inhibitors, and radiation treatment.

In certain embodiments, the anti-inflammatory agents include matrixmetalloproteinase inhibitors, inhibitors of pro-inflammatory cytokines(e.g., anti-TNF molecules, TNF soluble receptors, and IL1) non-steroidalanti-inflammatory drugs (NSAIDs) such as prostaglandin synthaseinhibitors (e.g., choline magnesium salicylate and salicylsalicyclicacid), COX-1 or COX-2 inhibitors, or glucocorticoid receptor agonistssuch as corticosteroids, methylprednisone, prednisone, or cortisone.

The compounds or compositions provided herein, or pharmaceuticallyacceptable salta thereof, may be administered simultaneously with, priorto, or after administration of one or more of the above agents.

Pharmaceutical compositions containing a compound provided herein orpharmaceutically acceptable salt thereof, and one or more of the aboveagents are also provided.

Also provided is a combination therapy that treats or prevents the onsetof the symptoms, or associated complications of cancer and relateddiseases and disorders comprising the administration to a subject inneed thereof, of one of the compounds or compositions disclosed herein,or pharmaceutically acceptable salts, solvates, hydrates or clathratesthereof, with one or more anti-cancer agents.

G. Preparation of the Compounds

Starting materials in the synthesis examples provided herein are eitheravailable from commercial sources or via literature procedures (e.g.,March Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,(1992) 4th Ed.; Wiley Interscience, New York). All commerciallyavailable compounds were used without further purification unlessotherwise indicated. CDCl₃ (99.8% D, Cambridge Isotope Laboratories) wasused in all experiments as indicated. Proton (¹H) nuclear magneticresonance (NMR) spectra were recorded on a Bruker Avance 300 MHz NMRspectrometer. Significant peaks are tabulated and typically include:number of protons, and multiplicity (s, singlet; d, double; t, triplet;q, quartet; m, multiplet; br s, broad singlet). Chemical shifts arereported as parts per million (δ) relative to tetramethylsilane. Lowresolution mass spectra (MS) were obtained as electrospray ionization(ESI) mass spectra, which were recorded on a Shimadzu HPLC/MS instrumentusing reverse-phase conditions (acetonitrile/water, 0.05% acetic acid).Preparative HPLC was performed using Varian HPLC systems and Phenomenexcolumns. Flash chromatography was performed using Merck Silica Gel 60(230-400 mesh) following standard protocol (Still et al. (1978) J. Org.Chem. 43:2923).

It is understood that in the following description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds under standardconditions.

It will also be appreciated by those skilled in the art that in theprocess described below the functional groups of intermediate compoundsmay need to be protected by suitable protecting groups. Such functionalgroups include hydroxy, amino, mercapto and carboxylic acid. Suitableprotecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl(e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl),tetrahydropyranyl, benzyl, and the like. Suitable protecting groups foramino, amidino and guanidino include t-butoxycarbonyl,benzyloxycarbonyl, and the like. Suitable protecting groups for mercaptoinclude —C(O)—R (where R is alkyl, aryl or aralkyl), p-methoxybenzyl,trityl and the like. Suitable protecting groups for carboxylic acidinclude alkyl, aryl or aralkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are well-known to those skilled in the art and asdescribed herein. The use of protecting groups is described in detail inGreen, T. W. and P. G. M. Wutz, Protective Groups in Organic Synthesis(1991), 2nd Ed., Wiley-Interscience.

One of ordinary skill in the art could easily ascertain which choicesfor each substituent are possible for the reaction conditions of eachScheme. Moreover, the substituents are selected from components asindicated in the specification heretofore, and may be attached tostarting materials, intermediates, and/or final products according toschemes known to those of ordinary skill in the art.

Also it will be apparent that the compounds provided herein could existas one or more isomers, that is E/Z isomers, enantiomers and/ordiastereomers.

Compounds of formula (I) may be generally prepared as depicted in thefollowing schemes, unless otherwise noted, the various substituents areas defined elsewhere herein.

Standard abbreviations and acronyms as defined in J. Org. Chem. 200772(1): 23A-24A are used herein. Exemplary abbreviations and acronymsused herein are as follows:

DCM—dichloromethane

DIEA—N,N-diisopropylethylamine

EtOAc—ethyl acetateEDCI—1-ethyl-3-(3′-dimethylaminopropyl)carbodiimideEtOH—ethanolFBS—fetal bovine serumHOAc—acetic acidMeOH—methanolmin—minute(s)

Activated quinazoline derivatives having one or more R¹ substituents(where each R¹ substitutent may or may not differ from the other R¹substitutent(s)) are either commercially available or may be preparedaccording to Scheme 1. Activated quinazoline may be synthesized startingfrom anthranilic esters (1c, where R is alkyl) which are eithercommercially available, or are prepared from benzoic ester derivatives(1a, where R is alkyl), which undergoes classical nitration to yield the2-nitro benzoic ester derivative (1b) which is followed by separationfrom any undesired regioisomers by crystallization or chromatography.For the reduction step, the 2-nitro intermediate in a suitable solventsuch as water, C₁-C₄ alcohol, ethyl acetate or N,N-dimethylformamide,may be reacted with reducing agents such as hydrogen gas in the presenceof noble metal catalyst, sodium dithionite, tin chloride, tin or ironmetal in the presence of acid, and the like, to yield the anthranilicester intermediate (1c).

There are many synthetic routes known to one skilled in the art that maybe used to prepare the 4-hydroxy quinazoline derivative (1d). One routethat may be used is the condensation of a suitable anthranilic esterderivative with formamide or a suitable formamide derivative such asformamidine hydrochloride in a suitable solvent such as ethanol at atemperature from 100° C. to 130° C., normally in the presence of an acidsuch as acetic acid (See, for example, Ballard et al. Bioorganic &Medicinal Chemistry Letters 2006, 16, 1633-1637) to yield 1d. Followingisolation, the intermediate 4-hydroxyquinazoline derivative may betreated with an activating agent such as a phosphoric oxytrihalide or anaryl- or alkylsulfonyl halide to produce the activated quinazolineintermediate (1e) (See, for example, Takase et al. J. Med. Chem. 1994,37, 2106-2111).

Phenyleneamine derivatives (2b) may be prepared according to Scheme 2 byreaction of corresponding activated quinazoline derivatives (1e) withthe unprotected meta-hydroxy-(X═O) or meta-mercapto (X═S) aniline (2a)in a suitable solvent such as tetrahydrofuran or N,N-dimethylformamideat a temperature from 40° C. to 85° C., with formation (preferablypreformation) of the oxa or sulfa anion with a base such as sodiumhydride or cesium carbonate.

Alternatively, as will be apparent to one skilled in the art, the freeamino group of 2a in Scheme 2 may be introduced in the form of anappropriate precursor, for example nitro or protected amino, followed byliberation of the free amine by nitro reduction or amine deprotection,respectively, to furnish 2b.

Diaryl ureas having the Formula I may be prepared according to Scheme 3by the reaction of a phenyleneamine derivative (2b) (which may beprepared as described in Scheme 2), with an activated arylcarbamic acidderivative (3b, where Ar can be aryl or heteroaryl, which may beprepared as described below), where Z is a leaving group such as halo oroptionally substituted phenoxy, for example.

Alternatively, diaryl ureas having the Formula I may be preparedaccording to Scheme 4 when R⁵═H. Phenyleneamine (2b) is treated with anaryl isocyanate (4b, where Ar can be aryl or heteroaryl) in a suitablesolvent such as tetrahydrofuran at a temperature from 25° C. to 60° C.,optionally in the presence of a base.

Alternatively, compounds having the Formula I may be prepared accordingto scheme 5 by the reaction of a hydroxy-(X═O) or mercapto-(X═S)substituted diaryl urea (5a, where Ar can be aryl or heteroaryl, whichmay be prepared as described below), with an activated quinazolinederivative (1e, where Y is a leaving group such as halo, aryl- oralkylsulfonate, which may be prepared as described in Scheme 1), in asuitable solvent such as tetrahydrofuran at a temperature from 40° C. to80° C., normally in the presence of a base such as sodium hydride orcesium carbonate.

In certain embodiments, R¹ substituents of diaryl ureas having theFormula I, prepared as shown in Schemes 3, 4 and 5, may be furthermodified. For example, R¹ containing a haloalkyl moiety may betransformed to, for example, an aminoalkyl, alkoxyalkyl or thioalkyl, bytreatment with, respectively, amines, alkoxides or thiolates.Alternatively, R¹ containing a carboxylic acid or carboxylic ester groupmay be transformed to the corresponding amides, amidines, alcohol,aldeyhdes, ketones, and aldehyde or ketone derivatives including oximes,hydrazones and the like. Where R¹ contains a hydroxy group, the hydroxygroup may be derivatized to form the corresponding ester (by acylation),corresponding carbamate (by carbamylation), corresponding imidate andthe like.

Arylcarbamoyl derivatives may be prepared as in Scheme 6 by treatment ofcorresponding aryl amines (6a, R⁵═H) with a reagent such as an arylchloroformate in a solvent such as tetrahydrofuran or dichloromethane inthe presence of a base such as potassium carbonate at a temperature from25° C. to 60° C. to give the corresponding aryl carbamate (6b or 3b,where Z may be, for example, phenoxy). When R⁵≠H, phosgene,trichloromethyl chloroformate, or bis-trichloromethyl carbonate may beused to prepare arylcarbamoyl chloride variants (6c where Hal ishalogen, or 3b, where Z may be, for example, halo).

Scheme 7 shows the preparation of isocyanate derivatives (4b) which areprepared by treatment of corresponding primary aryl amines (7a) (whereAr may be aryl or heteroaryl) with phosgene, trichloromethylchloroformate, or bis-trichloromethyl carbonate in a solvent such astoluene in the presence of a base such as triethylamine at a temperaturefrom 25° C. to 110° C. to give the corresponding isocyanate (4b) (whereAr may be aryl or heteroaryl).

Aryl amine derivatives (7a), wherein Ar is a 5-membered heteroaromaticring, may be prepared by condensation of appropriate fragments andprecursors by methods well known in the art and described in texts suchas Gilchrist, T. L., Heterocyclic Chemistry (1992), 2nd Ed., LongmanScientific & Technical and John Wiley & Sons. Scheme 8 shows one examplewhere Ar is 5-substituted-3-aminoisoxazole, whereby an appropriate3-oxonitrile (8a) is treated with hydroxylamine under appropriateconditions of pH and temperature which is described, for example, inTakase et al. Heterocycles 1991 32(6), 1153-1158, to afford the desiredaryl amine product (8b). This method is particularly applicable forcases in which the atom of 1e directly attached to the aromatic ring ishighly substituted, for example, is an α,α-dialkyl substituent (SeeTakase et al. Heterocycles 1991 32(6), 1153-1158).

Scheme 9 shows an example for the case where Ar is3-substituted-5-aminoisoxazole, whereby an appropriate 3-oxonitrile 9ais treated with hydroxylamine under appropriate conditions of pH andtemperature, as described again in Takase et al. Heterocycles 199132(6), 1153-1158, to afford the desired aryl amine product (9b). Thismethod is particularly applicable for cases in which the atom of R¹⁰directly attached to the aromatic ring is not highly substituted, forexample, is not an α,α-dialkyl substituent (See Eddington et al. Eur. J.Med. Chem. 2002 37, 635-648), or when le contains one or more highlyelectron-withdrawing groups, eg, fluorine, or under special conditionsof pH and solvent, such as ethanol and water mixture as described in EP0220947.

Scheme 10 shows an example for the case where Ar is a2,5-disubstituted-3-aminopyrazole, whereby an appropriate 3-oxonitrile(10a) is treated with a monosubstituted hydrazine under appropriateconditions of pH and temperature to afford the desired aryl amineproduct (10b).

Depending on R¹⁰, in order to influence the yield and regiochemicaloutcome of the condensation reaction, 3-oxonitrile (10a) may beproductively replaced in the foregoing schemes by oxo-protectedderivatives of (10a), such as an enol ether derivative (10c, R=loweralkyl or substituted silyl) or a ketal derivative (10d, R=lower alkyl ortaken together, an alkylene derivative to form a ketal ring). Thesederivatives are prepared from 3-oxonitrile under standard conditions,for example as described in Chan et al. Synthesis 1983 203-205.

Scheme 11 illustrates preparation of the requisite 3-oxonitriles (10a)by reaction of an R¹⁰-containing carboxylic ester (11a) with an akalimetal salt of acetonitrile (11b) (See, for example, U.S. Pat. No.4,728,743).

The subject matter has been described in an illustrative manner, and itis to be understood that the terminology used is intended to be in thenature of description rather than of limitation. Thus, it will beappreciated by those of skill in the art that conditions such as choiceof solvent, temperature of reaction, volumes, reaction time may varywhile still producing the desired compounds. In addition, one of skillin the art will also appreciate that many of the reagents provided inthe following examples may be substituted with other suitable reagents.See, e.g., Smith & March, Advanced Organic Chemistry, 5^(th) ed. (2001).Such changes and modifications, including without limitation thoserelating to the chemical structures, substituents, derivatives,intermediates, syntheses, formulations and/or methods of use providedherein, may be made without departing from the spirit and scope thereof.U.S. patents and publications referenced herein are incorporated byreference.

EXAMPLES

The embodiments described above are intended to be merely exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the claimed subject matter and areencompassed by the appended claims.

Example 1 Preparation Of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 1A: preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea: to THF (300 ml,degassed w/ argon) was added 3-aminophenol (4.36 g, 40 mmol) and5-tert-butyl-3-isocyanatoisoxazole (6.64 g, 40 mmol) and the mixture washeated at 50° C. overnight. After cooling to room temperature, thereaction was concentrated in vacuo, and the resulting foam purified bycolumn chromatography (25-75% EtOAc/hexanes) to give1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (8.81 g, 32 mmol,80%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.39 (s, 1h), 9.37 (s, 1h), 8.69 (s,1h), 7.06 (t, 1h), 7.01 (s, 1h), 6.78 (d, 1h), 6.49 (s, 1 h), 6.41 (d, 1h), 1.29 (s, 9h); LC-MS (ESI) m/z 275 (M+H)⁺.

Example 1B step 1: preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea:to a slurry of potassium tert-butoxide (6.73 g, 60 mmol) in THF (300 ml)was added the phenol from example 1a (8.25 g, 30 mmol), and the solutionstirred at room temperature for 1 hour, at which point4-chloro-6,7-dimethoxyquinazoline (6.74 g, 30 mmol) was added, followedby K₂CO₃ (4.1 g, 30 mmol). After stirring at room temperature for 72hours, the reaction was concentrated in vacuo. The resulting solid wasdiluted with EtOAc, the organic layer washed with water, dried overMgSO₄, filtered and concentrated in vacuo. The crude product waspurified by column chromatography (15-100% EtOAc/hexanes) to give1-(5-tert-butylisoxazol-3-yl)-3-(3-(2-chloro-6,7-dimethoxyquinazolin-4-yloxy)phenyl)ureaas a white solid.

Example 1B step 2: the compound was dissolved in EtOAc (50 ml) and 4NHCl in dioxane (5 ml, 20 mmol) was added. The mixture was sonicated,stirred and concentrated in vacuo to give the product (6.23 g, 12.5mmol, 42%) as the mono-hydrochloride. ¹H NMR (300 MHz, DMSO-d₆) δ 9.72(s, 1h), 9.44 (s, 1h), 8.73 (s, 1h), 7.65-7.60 (m, 2h), 7.45-7.38 (m,2h), 7.29 (d, 1h), 6.98 (d, 1h), 6.48 (s, 1h), 4.02 (s, 3h), 4.00 (s,3h), 1.28 (s, 9h); LC-MS (ESI) m/z 464 (M+H)⁺.

Example 2 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxyquinazolin-4-yloxy)phenyl)urea

To 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A(275 mg, 1 mmol) was added 4-chloro-6-methoxyquinazoline (194 mg, 1mmol) according to the procedure described in Example 1B Step 1. Theresulting compound was dissolved in EtOAc and 4N HCl in dioxane wasadded. The mixture was sonicated, stirred and concentrated in vacuo togive1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxyquinazolin-4-yloxy)phenyl)ureaas the mono-hydrochloride (299 mg, 0.64 mmol, 64%). ¹H NMR (300 MHz,DMSO-d₆) δ 9.65 (s, 1H), 9.20 (s, 1H), 8.65 (s, 1H), 7.95 (d, 1H),7.75-7.60 (m, 3H), 7.42 (t, 1H), 7.29 (d, 1H), 6.98 (d, 1H), 6.48 (s,1H), 3.98 (s, 3H), 1.29 (s, 9H); LC-MS (ESI) m/z 434 (M+H)⁺.

Example 3 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxyquinazolin-4-yloxy)phenyl)urea

To 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A(137 mg, 0.5 mmol) was added 4-chloro-7-methoxyquinazoline (97 mg, 0.5mmol) according to the procedure described in Example 1B. The resultingcompound was dissolved in EtOAc (5 mL) and 4N HCl in dioxane (0.2 mL,0.8 mmol) was added. The mixture was sonicated, stirred and concentratedin vacuo to give1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxyquinazolin-4-yloxy)phenyl)ureaas the mono-hydrochloride (103 mg, 0.22 mmol, 44%). ¹H NMR (300 MHz,DMSO-d₆) δ 9.63 (s, 1H), 9.15 (s, 1H), 8.69 (s, 1H), 8.28 (d, 1H), 7.58(s, 1H), 7.45-7.35 (m, 3H), 7.27 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H),3.98 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 434 (M+H)⁺.

Example 4 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-difluoroquinazolin-4-yloxy)phenyl)urea

Example 4A Step 1: To a stirring mixture of formamide (10 mL) andglacial acetic acid (2.5 mL) was added 2-amino-4,5-difluorobenzoic acid(2.0 g, 11.6 mmol) and the solution stirred at 125° C. for 8 hours.After cooling to room temperature, the reaction was diluted with H₂O(100 mL) and the resulting solid filtered and dried under vacuum to give6,7-difluoro-4-hydroxyquinazoline (1.77 g, 9.7 mmol, 84%). ¹H NMR (300MHz, DMSO-d₆) δ 12.49 (br s, 1H), 8.15 (s, 1H), 8.04 (dd, 1H), 7.76 (dd,1H); LC-MS (ESI) m/z 183 (M+H)⁺.

Example 4A Step 2: To POCl₃ (15 mL) was added6,7-difluoro-4-hydroxyquinazoline (910 mg, 5 mmol) followed bytriethylamine (700 uL, 5 mmol). The solution was then heated at 100° C.for 4 hours and concentrated in vacuo. The resulting sludge wastriturated with EtOAc (2×100 mL), and the combined decanted org layerswere flushed through a plug of silica gel to give4-chloro-6,7-difluoroquinazoline (870 mg, 4.35 mmol, 87%). LC-MS (ESI)m/z 201 (M+H)⁺.

Example 4B Step 1: To the intermediate1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A(110 mg, 0.4 mmol) was added 4-chloro-6,7-difluoroquinazoline from theprevious step (80 mg, 0.4 mmol) according to the procedure described inExample 1B Step 1, to afford the title compound.

Example 4B Step 2: The title compound was dissolved in EtOAc and 4N HClin dioxane was added. The mixture was sonicated, stirred andconcentrated in vacuo to give1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-difluoroquinazolin-4-yloxy)phenyl)ureaas the mono-hydrochloride (88 mg, 0.18 mmol, 46%). ¹H NMR (300 MHz,DMSO-d₆) δ 9.61 (s, 1H), 9.11 (s, 1H), 8.68 (s, 1H), 8.42 (dd, 1H), 8.11(dd, 1H), 7.60 (s, 1H), 7.42 (t, 1H), 7.30 (d, 1H), 6.98 (d, 1H), 6.49(s, 1H), 1.28 (s, 9H); LC-MS (ESI) m/z 440 (M+H)⁺.

Example 5 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(5-methylquinazolin-4-yloxy)phenyl)urea

Example 5A Step 1: 2-amino-6-methylbenzoic acid (2.0 g, 13.2 mmol) wasreacted using the procedure described in Example 4A Step 1 to give4-hydroxy-5-methylquinazoline (1.6 g, 10.0 mmol, 76%). ¹H NMR (300 MHz,DMSO-d₆) δ 12.04 (br s, 1H), 8.00 (s, 1H), 7.63 (t, 1H), 7.46 (d, 1H),7.26 (d, 1H), 2.82 (s, 3H); LC-MS (ESI) m/z 161 (M+H)⁺.

Example 5A Step 2: 4-hydroxy-5-methylquinazoline (600 mg, 3.75 mmol) wasreacted using the procedure described in Example 4A Step 2 to give4-chloro-5-methylquinazoline (585 mg, 3.28 mmol, 87%). LC-MS (ESI) m/z179 (M+H)⁺.

Example 5B Step 1: To1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A(83 mg, 0.3 mmol) was added 4-chloro-5-methylquinazoline from theprevious step (53 mg, 0.3 mmol) using the procedure described in Example1B Step 1, to afford the title compound.

Example 5B Step 2: Using the procedure described in Example 1B Step 2,the compound from the previous step was dissolved in EtOAc and 4N HCl indioxane was added. The mixture was sonicated, stirred and concentratedin vacuo to give1-(5-tert-butylisoxazol-3-yl)-3-(3-(5-methylquinazolin-4-yloxy)phenyl)ureaas the mono-hydrochloride (18 mg, 0.04 mmol, 14%). ¹H NMR (300 MHz,DMSO-d₆) δ 9.75 (s, 1H), 9.51 (s, 1H), 8.78 (s, 1H), 7.90 (t, 1H), 7.84(t, 1H), 7.62-7.55 (m, 2H), 7.42 (t, 1H), 7.28 (d, 1H), 6.99 (d, 1H),6.49 (s, 1H), 2.92 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 418 (M+H)⁺.

Example 6 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)phenyl]ureahydrochloride

Example 6A Step 1: A mixture of methyl vanillate (6.376 g, 35 mmol),bromoethane (4.359 g, 40 mmol), and K₂CO₃ (5.528 g, 40 mmol) in DMF (40mL) was heated at 70° C. for 2 hours. The reaction mixture was quenchedwith water, filtered, washed with water, and dried under vacuum withP₂O₅ to give methyl 4-ethoxy-3-methoxybenzoate as white solid (7.123 g,97%). ¹H NMR (300 MHz, CDCl₃) δ 7.66 (dd, 1H), 7.55 (d, 1H), 6.88 (d,1H), 4.17 (q, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 1.50 (t, 3H); LC-MS (ESI)m/z 211 (M+H)⁺.

Example 6A Step 2: To a solution of methyl 4-ethoxy-3-methoxybenzoate(7.12 g, 33.9 mmol) and acetic anhydride (40 mL) in acetic acid (40 mL)at room temperature was dropped fume nitric acid (90%, 3.15 g). Afterstirring at room temperature for 15 minutes, it was heated at 50° C. for1 hour. The reaction mixture was poured into ice and a solid was formed.It was filtered, washed with water, and dried under vacuum with P₂O₅ togive methyl 4-ethoxy-5-methoxy-2-nitrobenzoate as white solid (8.392 g,97%). ¹H NMR (300 MHz, CDCl₃) δ 7.44 (s, 1H), 7.07 (s, 1H), 4.19 (q,2H), 3.98 (s, 3H), 3.91 (s, 3H), 1.52 (t, 3H); LC-MS (ESI) m/z 256(M+H)⁺.

Example 6A Step 3: A mixture of methyl4-ethoxy-5-methoxy-2-nitrobenzoate (8.38 g, 32.8 mmol) and Pd/C (10%,0.85 g) in MeOH (20 mL) was stirred under 1 atmosphere of hydrogen atroom temperature for 6 hours. The reaction mixture was filtered withCelite and washed with MeOH. The filtration was concentrated underreduced pressure to give methyl 2-amino-4-ethoxy-5-methoxybenzoate assolid (6.832 g, 92%). ¹H NMR (300 MHz, CDCl₃) δ 7.30 (s, 1H), 6.13 (s,1H), 5.56 (br, 2H), 4.08 (q, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 1.48 (t,3H); LC-MS (ESI) m/z 226 (M+H)⁺.

Example 6A Step 4: A mixture of methyl2-amino-4-ethoxy-5-methoxybenzoate (4.43 g, 19.7 mmol) and formamidinehydrochloride (2.255 g, 28 mmol) in formamide (20 mL) was heated at 130°C. for 8 hours. The reaction mixture was quenched with water, filtered,washed with water, and dried under vacuum with P₂O₅ to give7-ethoxy-6-methoxyquinazolin-4(3H)-one as solid (3.029 g, 70%). ¹H NMR(300 MHz, DMSO-d₆) δ 12.1 (br, 1H), 7.97 (s, 1H), 7.43 (s, 1H), 7.10 (s,1H), 4.16 (q, 2H), 3.87 (s, 3H), 1.38 (t, 3H); LC-MS (ESI) m/z 221(M+H)⁺.

Example 6A Step 5: A mixture of 7-ethoxy-6-methoxyquinazolin-4(3M-one(1.20 g, 5.45 mmol) and POCl₃ (3 mL), in toluene (10 mL) was heated at125° C. for 5 hours. It was concentrated under reduced pressure todryness. To it was added CH₂Cl₂ and it was washed with saturated NaHCO₃.The organic layer was dried over MgSO₄ and concentrated to give4-chloro-7-ethoxy-6-methoxyquinazoline as solid (1.254 g, 96%). ¹H NMR(300 MHz, CDCl₃) δ 8.91 (s, 1H), 7.52 (s, 1H), 7.42 (s, 1H), 4.34 (q,2H), 4.08 (s, 3H), 1.59 (t, 3H).

Example 6B Step 1: A mixture of1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A(0.2 g 0.73 mmol), 4-chloro-7-ethoxy-6-methoxyquinazoline from theprevious step (0.18 g, 0.75 mmol), and potassium tert-butoxide (0.252 g,2.25 mmol) in THF was stirred at room temperature overnight, and thenwas heated at 60° C. for 5 hours. The reaction was still found to beincomplete and additional1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (0.07 g, 0.025mmol) was added. The mixture was heated further at 60° C. overnight. Thereaction was quenched with water and extracted with EtOAc. Extracts weredried over MgSO₄ and concentrated under reduced pressure. It waspurified by silica gel chromatography with EtOAc/hexane as eluant toafford1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)phenyl]ureaas a solid (0.078 g). ¹H NMR (300 MHz, CDCl₃) δ 9.12 (br and s, 2H),8.61 (s, 1H), 7.64 (s, 1H), 7.54 (s, 1H), 7.31 (m, 3H), 7.0 (d, 1H),6.05 (s, 1H), 4.29 (q, 2H), 4.05 (s, 3H), 1.58 (t, 3H), 1.30 (s, 9H);LC-MS (ESI) m/z 478 (M+H)⁺.

Example 6B Step 2: To a solution of1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)phenyl]ureain MeOH and CH₂Cl₂ was added 1.0 M HCl in ethyl ether (2 equivalents).After solvent was concentrated under reduced pressure, to the residuewas added ethyl ether and a white solid was formed. It was filtered,washed with ethyl ether, and dried under vacuum with P₂O₅ to afford1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)phenyl]ureahydrochloride as a white solid (0.067 g, 16%). ¹H NMR (300 MHz, DMSO-d₆)δ 9.64 (s, 1H), 9.19 (s, 1H), 8.62 (s, 1H), 7.59 (s, 2H), 7.40 (m, 2H),7.26 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 4.27 (q, 2H), 3.99 (s, 3H),1.44 (t, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 478 (M+H)⁺.

Example 7 Preparation of1-(5-tert-Butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}ureahydrochloride

Example 7A Step 1: A mixture of methyl vanillate (6.376 g, 35 mmol),1-bromo-2-methoxyethane (5.56 g, 40 mmol), and K₂CO₃ (5.528 g, 40 mmol)in DMF (40 mL) were reacted according to the procedure described inExample 6A Step 1, to afford methyl3-methoxy-4-(2-methoxyethoxy)benzoate as a solid (8.394 g, 99.8%). ¹HNMR (300 MHz, CDCl₃) δ 7.65 (dd, 1H), 7.54 (d, 1H), 6.92 (d, 1H), 4.23(q, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.81 (t, 2H), 3.45 (s, 3H); LC-MS(ESI) m/z 241 (M+H)⁺.

Example 7A Step 2: Using the procedure described in Example 6A Step 2,methyl 3-methoxy-4-(2-methoxyethoxy)benzoate (8.39 g, 34.9 mmol) wasreacted with fuming nitric acid (90%, 3.15 g) in AcOH (60 mL) at 50° C.for 8 hours, to afford methyl5-methoxy-4-(2-methoxyethoxy)-2-nitrobenzoate as a yellow solid (7.956g, 80%). ¹H NMR (300 MHz, CDCl₃) δ 7.51 (s, 1H), 7.07 (s, 1H), 4.25 (t,2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.82 (t, 2H), 3.46 (s, 3H); LC-MS (ESI)m/z 286 (M+H)⁺.

Example 7A Step 3: According to the procedure described in Example 6AStep 3, a mixture of methyl5-methoxy-4-(2-methoxyethoxy)-2-nitrobenzoate (3.19 g, 11.2 mmol) andPd/C (10%, 0.3 g) in EtOAc (150 mL) was stirred under 1 atmosphere ofhydrogen at room temperature for 6 hours, to afford methyl2-amino-5-methoxy-4-(2-methoxyethoxy)benzoate as a solid (2.699 g, 95%).¹H NMR (300 MHz, CDCl₃) δ 7.30 (s, 1H), 6.17 (s, 1H), 5.55 (br, 2H),4.14 (t, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.79 (t, 2H), 3.44 (s, 3H);LC-MS (ESI) m/z 256 (M+H)⁺.

Example 7A Step 4: According to the procedure described in Example 6AStep 4, a mixture of methyl2-amino-5-methoxy-4-(2-methoxyethoxy)benzoate (2.69 g, 10.5 mmol) andformamidine hydrochloride (1.208 g, 15 mmol) in formamide (10 mL) washeated at 140° C. for 8 hours, to afford6-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one as a white solid(1.935 g, 74%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.1 (br, 1H), 7.98 (s, 1H),7.44 (s, 1H), 7.14 (s, 1H), 4.23 (t, 2H), 3.87 (s, 3H), 3.72 (t, 2H),3.32 (s, 3H); LC-MS (ESI) m/z 251 (M+H)⁺.

Example 7A Step 5: According to the procedure described in Example 6AStep 5, a mixture of 6-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one(7.83 g, 31.3 mmol) and POCl₃ (20 mL) in toluene (50 mL) was heated at125° C. for 5 hours, to afford4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline as a solid (8.098 g,96%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.88 (s, 1H), 7.49 (s, 1H), 7.41 (s,1H), 4.36 (t, 2H), 4.01 (s, 3H), 3.76 (t, 2H), 3.34 (s, 3H).

Example 7B: According to the procedure described in Example 50, amixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (4.405g, 16 mmol) from Example 1A,4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline from Example 7A (4.837g, 18 mmol), and Cs₂CO₃ (8.145 g, 16 mmol) in isopropanol (80 mL) washeated at 70° C. for 4 hours, to afford1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}ureaas a solid (5.548 g, 68.3%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s, 1H),9.00 (s, 1H), 8.57 (s, 1H), 7.58 (m, 2H), 7.41 (m, 2H), 7.25 (d, 1H),6.98 (d, 1H), 6.48 (s, 1H), 4.34 (t, 2H), 3.99 (s, 3H), 3.78 (t, 2H),3.35 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 508 (M+H)⁺.

Example 7C: The title compound was prepared as described in Example 6BStep 2 using1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}urea(5.545 g, 10.9 mmol) and 1.0 M HCl/Et₂O solution (1.3 eq.) in CH₂Cl₂(100 mL) and MeOH (10 mL), to afford1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}ureahydrochloride as a solid (5.723 g, 96.3%). ¹H NMR (300 MHz, DMSO-d₆) δ9.58 (s, 1H), 9.68 (s, 1H), 9.28 (s, 1H), 8.65 (s, 1H), 7.60 (m, 2H),7.41 (m, 2H), 7.27 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 4.35 (t, 2H),4.00 (s, 3H), 3.78 (t, 2H), 3.35 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z508 (M+H)⁺.

Example 8 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methylquinazolin-4-yloxy)phenyl)urea

Example 8A Step 1: 2-Amino-5-methylbenzoic acid (2.0 g, 13.2 mmol) wasreacted according to the procedure described in Example 4A Step 1 togive 4-hydroxy-6-methylquinazoline (1.6 g, 10.0 mmol, 76%). ¹H NMR (300MHz, DMSO-d₆) δ 12.16 (br s, 1H), 8.03 (d, 1H), 7.92 (s, 1H), 7.65 (dd,1H), 7.57 (dd, 1H), 2.45 (s, 3H); LC-MS (ESI) m/z 161 (M+H)⁺.

Example 8A Step 2: 4-Hydroxy-6-methylquinazoline (500 mg, 3.12 mmol) wasreacted according to the procedure described in Example 4A Step 2 togive 4-chloro-6-methylquinazoline (546 mg, 3.05 mmol, 98%). LC-MS (ESI)m/z 179 (M+H)⁺.

Example 8B Step 1: The title compound was prepared using1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A(83 mg, 0.3 mmol) and 4-hydroxy-6-methylquinazoline from the previousstep (53 mg, 0.3 mmol) according to the procedure described in Example1B Step 1 to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methylquinazolin-4-yloxy)phenyl)urea.

Example 8B Step 2: As in Example 1B Step 2, the product from theprevious step was dissolved in EtOAc and 4N HCl in dioxane was added.The mixture was sonicated, stirred and concentrated in vacuo to give1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methylquinazolin-4-yloxy)phenyl)ureaas the mono-hydrochloride (101 mg, 0.24 mmol, 80%). ¹H NMR (300 MHz,DMSO-d₆) δ 9.69 (s, 1H), 9.34 (s, 1H), 8.75 (s, 1H), 8.21 (s, 1H),7.97-7.91 (m, 2H), 7.60 (d, 1H), 7.42 (t, 1H), 7.31 (d, 1H), 6.99 (d,1H), 6.48 (s, 1H), 2.61 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 418(M+H)⁺.

Example 9 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)urea

Example 9A Step 1: To a mixture of 4-fluoro-3-methoxyaniline (2.0 g,14.2 mmol) in CH₂Cl₂ (20 mL) at 0° C. was added 1.0 M solution of BBr₃in CH₂Cl₂ (40 mL). It was stirred overnight, at which time thetemperature was raised to room temperature. To it was added MeOH and thesolvents were removed under reduced pressure. To the residue was addedwater, basified with saturated NaHCO₃, and extracted with EtOAc.Extracts were washed with brine, dried over MgSO₄, and concentratedunder reduced pressure to afford 5-amino-2-fluorophenol as solid (1.3 g,73%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 6.81 (dd, 1H), 6.34 (dd,1H), 6.04 (dd, 1H), 4.63 (br, 2H).

Example 9A Step 2: A mixture of 5-amino-2-fluorophenol (1.3 g, 10.2mmol) and 5-tert-butyl-3-isocyanatoisoxazole (1.7 g, 10.2 mmol) intoluene (60 mL) was heated at 70° C. overnight. The solid was filteredand dried under vacuum to afford1-(5-tert-butylisoxazol-3-yl)-3-(4-fluoro-3-hydroxyphenyl)urea as solid.

Example 9B: In a sealed reaction vessel the phenol from the previousstep (131 mg, 0.45 mmol) was dissolved in dry THF (2 mL). This was addedto a suspension of potassium tert-butoxide (55 mg, 0.49 mmol) in THF (5mL) at 0° C. The reaction was allowed to slowly warm to roomtemperature. After stirring for 30 minutes, the4-chloro-6,7-dimethoxyquinazoline was added and the reaction stirred atroom temperature for 2 hours, then at 50° C. overnight. The reaction wasstill incomplete, so cesium carbonate (320 mg, 0.98 mmol) and thereaction heated to 80° C. for 6 hours. The reaction was partitionedbetween ethyl acetate and water, and then extracted twice. The extractswere combined, dried over magnesium sulfate, filtered and concentrated.The resulting oil was purified by silica gel chromatography eluting witha gradient of ethyl acetate/dichloromethane 0-25% over 60 minutes. Themajor peak was collected and concentrated to afford 50 mg of the titlecompound. This was then dissolved in dry dichloromethane and 1 M HCl inether (0.5 mL) was added and the solution concentrated to dryness, togive 50 mg of the hydrochloride salt. ¹H NMR (300 MHz, DMSO-d₆) δ 9.80(s, 1H), 9.70 (s, 1H), 8.73 (s, 1H), 7.71 (m, 1H), 7.64 (s, 1H), 7.47(s, 1H), 7.37 (m, 2H), 6.48 (s, 1H), 4.00 (s, 6H), 1.30 (s, 9H). LC-MS(ESI) m/z 482 (M+H)⁺.

Example 10 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(4-chloro-3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 10A: A mixture of 5-amino-2-chlorophenol (1.0 g, 6.97 mmol) and5-tert-butyl-3 isocyanatoisoxazole (1.16 g, 6.97 mmol) in toluene (40mL) was heated at 70° C. overnight. It was purified by silica gelchromatography with 0-25% EtOAc/hexane as eluants to afford1-(5-tert-butylisoxazol-3-yl)-3-(4-chloro-3-hydroxyphenyl)urea as solid.

Example 10B: In a sealed reaction vessel the phenol from the previousstep (138 mg, 0.44 mmol) was dissolved in 4 mL of dry THF, and cesiumcarbonate (289 mg, 0.89 mmol) was added. To this mixture4-chloro-6,7-dimethoxyquinazoline (100 mg, 0.44 mmol) was added and thereaction heated to 60° C. overnight. The reaction was then partitionedbetween ethyl acetate and water and extracted twice. The extractscombined, dried over magnesium sulfate, filtered, and concentrated. Theresulting concentrate was purified by silica gel chromatography elutingwith a gradient of ethyl acetate/dichloromethane 0-25% over 60 minutes.The main peak was collected and concentrated to afford 70 mg of thetitle compound. The compound was then dissolved in anhydrousdichloromethane and 1 M HCl (0.5 mL) was added and the solutionevaporated to dryness to give the hydrochloride salt weighing 67 mg. ¹HNMR (300 MHz, DMSO-d₆) δ 9.86 (d, 2H), 8.75 (s, 1H), 7.75 (s, 1H), 7.65(s, 1H), 7.58 (d, 1H), 7.48 (s, 1H), 7.32 (d, 1H), 6.49 (s, 1H), 4.00(s, 6H), 1.30 (s, 9H). LC-MS (ESI) m/z 498 (M+H)⁺.

Example 11 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)phenyl)urea

Example 11A Step 1: A mixture of 4,5-dimethoxy-2-nitrobenzoic acid (20.6g, 90.7 mmol) in 20% KOH solution (136 mL) was heated at 100° C. for 12hours. After it was cooled with ice, it was acidified with concentratedHCl to pH 2. It was filtered, washed with CH₂Cl₂ and EtOAc, and driedover vacuum to afford 5-hydroxy-4-methoxy-2-nitrobenzoic acid as solid(18.38 g, 95%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.29 (s, 1H), 6.90 (s, 1H),4.8 (br, 1H), 3.77 (s, 3H).

Example 11A Step 2: To a suspension of5-hydroxy-4-methoxy-2-nitrobenzoic acid (8.0 g, 37.5 mmol) in methanolwas added concentrated sulfuric acid (3 drops) and it was heated at 80°C. overnight. After solvent was removed under reduced pressure, to itwas added water and EtOAc. The organic layer was washed with saturatedNaHCO₃ solution, dried over MgSO₄, and concentrated under reducedpressure to afford methyl 5-hydroxy-4-methoxy-2-nitrobenzoate as a solid(3.86 g, 45%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.96 (s, 1H), 7.63 (s, 1H),7.08 (s, 1H), 3.91 (s, 3H), 3.81 (s, 3H).

Example 11A Step 3: According to the procedure described in Example 6AStep 3, a mixture of methyl 5-hydroxy-4-methoxy-2-nitrobenzoate (3.88 g,17.1 mmol) and Pd/C in EtOAc (100 mL) was stirred under 1 atmosphere ofhydrogen at room temperature overnight, to afford methyl2-amino-5-hydroxy-4-methoxybenzoate as a solid (3.1 g, 92%). ¹H NMR (300MHz, DMSO-d₆) δ 8.31 (s, 1H), 7.08 (s, 1H), 6.31 (s, 1H), 6.24 (s, 1H),3.74 (s, 3H), 3.72 (s, 3H).

Example 11A Step 4: A mixture of methyl2-amino-5-hydroxy-4-methoxybenzoate (3.1 g, 15.7 mmol) and AcOH (7.1 mL)in formamide (15.5 mL) was heated at 140° C. overnight. To it was addedwater (20 mL) and filtered to afford6-hydroxy-7-methoxyquinazoline-4(3H)-one as a solid (2.7 g, 89%). ¹H NMR(300 MHz, DMSO-d₆) δ 9.82 (s, 1H), 7.9 (s, 1H), 7.4 (s, 1H), 7.1 (s,1H), 3.9 (s, 3H).

Example 11A Step 5: A mixture of6-hydroxy-7-methoxyquinazoline-4(3H)-one (1.0 g, 5.2 mmol) and Cs₂CO₃(1.69 g, 5.2 mmol) in H₂O:MeCN:MeOH (10:5:1, 20 mL) was stirred at roomtemperature for 30 minutes and to it was added bromoethane (0.567 g, 5.2mmol). Then, it was stirred at 60° C. two days. It was filtered toafford 6-ethoxy-7-methoxyquinazolin-4(3H)-one as a solid (0.550 g, 48%).¹H NMR (300 MHz, DMSO-d₆) δ 8.0 (s, 1H), 7.91 (s, 1H), 7.4 (d, 1H), 7.1(d, 1H), 4.15 (t, 2H), 3.9 (s, 3H), 1.4 (t, 3H).

Example 11A Step 6: According to the procedure described in Example 6AStep 5, a mixture of 6-ethoxy-7-methoxyquinazolin-4(3H)-one (0.52 g,2.36 mmol) and POCl₃ (1 mL) in toluene (10 mL) was heated at 125° C. for3.5 hours. The residue was purified by silica gel chromatography with0-25% EtOAc/hexane as eluants to afford4-chloro-6-ethoxy-7-methoxyquinazoline as a solid (0.19 g, 34%). ¹H NMR(300 MHz, CDCl₃) δ 8.9 (s, 1H), 7.4 (s, 1H), 7.3 (s, 1H), 4.3 (t, 2H),4.1 (s, 3H), 1.6 (t, 3H).

Example 11B: The title compound was prepared using the procedure forExample 10B but using the intermediate4-chloro-6-ethoxy-7-methoxyquinazoline (97 mg, 0.35 mmol) from theprevious step and 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)ureafrom Example 1A (84 mg, 0.35 mmol). To this reaction cesium carbonate(115 mg, 0.35 mmol) was added and the reaction heated to 60° C.overnight. The title compound was purified as above using a gradient ofethyl acetate/dichloromethane 0-50% over 75 minutes. The correspondinghydrochloride salt was prepared using the procedure described in Example10B. ¹H NMR (300 MHz, DMSO-d₆) δ 9.81 (s, 1H), 9.69 (s, 1H), 8.84 (s,1H), 7.64 (m, 2H), 7.43 (m, 2H), 7.29 (m, 1H), 7.01 (m, 1H), 6.49 (s,1H), 4.30 (m, 2H), 4.04 (s, 3H), 1.46 (m, 3H), 1.16 (s, 9H); LC-MS (ESI)m/z 478 (M+H)⁺.

Example 12 Preparation of1-{3-[6,7-bis(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-(5-tert-butylisoxazol-3-yl)ureahydrochloride

Example 12A Step 1: According to the procedure described in Example 6AStep 1, a mixture of ethyl 3,4-dihydroxybenzoate (5.465 g, 30 mmol),1-bromo-2-methoxyethane (9.174 g, 66 mmol), and K₂CO₃ (9.122 g, 66 mmol)in DMF (50 mL) was heated at 50° C. for 5 hours, to afford ethyl3,4-bis(2-methoxyethoxy)benzoate as a solid (7.872 g, 88%). ¹H NMR (300MHz, CDCl₃) δ 7.67 (dd, 1H), 7.59 (d, 1H), 6.91 (d, 1H), 4.35 (q, 2H),4.22 (m, 4H), 3.80 (m, 4H), 3.46 (s, 6H), 1.38 (t, 3H); LC-MS (ESI) m/z299 (M+H)⁺.

Example 12A Step 2: According to the procedure described in Example 6AStep 2, to a solution of ethyl 3,4-bis(2-methoxyethoxy)benzoate (7.87 g,26.4 mmol) in AcOH (50 mL) was added HNO₃ (90%, 4 mL) and the mixturewas heated at 50° C. for 5 hours, to afford ethyl4,5-bis(2-methoxyethoxy)-2-nitrobenzoate as an oil (8.531 g, 94%). ¹HNMR (300 MHz, CDCl₃) δ 7.51 (s, 1H), 7.12 (s, 1H), 4.37 (q, 2H), 4.25(m, 4H), 3.80 (m, 4H), 3.45 (s, 6H), 1.35 (t, 3H); LC-MS (ESI) m/z 344(M+H)⁺.

Example 12A Step 3: According to the procedure described in Example 6AStep 3, a mixture of ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate(8.53 g, 24.8 mmol) and Pd/C (10%, 0.85 g) in EtOAc (150 mL) was stirredunder 1 atmosphere of hydrogen at room temperature overnight, to affordethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate as an oil (7.15 g, 92%).¹H NMR (300 MHz, CDCl₃) δ 7.44 (s, 1H), 6.15 (s, 1H), 5.60 (br, 2H),4.30 (q, 2H), 4.13 (t, 2H), 4.08 (t, 2H), 3.78 (t, 2H), 3.73 (t, 2H),3.45 (s, 6H), 1.36 (t, 3H); LC-MS (ESI) m/z 314 (M+H)⁺.

Example 12A Step 4: According to the procedure described in Example 6AStep 4, a mixture of ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate(7.15 g, 22.8 mmol) and formamidine hydrochloride (2.012 g, 25 mmol) informamide (20 mL) was heated at 130° C. for 12 hours, to afford6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one as a solid (3.75 g, 56%).¹H NMR (300 MHz, CDCl₃) δ 10.89 (br, 1H), 8.00 (s, 1H), 7.62 (s, 1H),7.16 (s, 1H), 4.29 (t, 4H), 3.86 (t, 4H), 3.48 (s, 6H); LC-MS (ESI) m/z295 (M+H)⁺.

Example 12A Step 5: According to the procedure described in Example 6AStep 5, a mixture of 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (2.28g, 7.7 mmol) and POCl₃ (10 mL) in toluene (30 mL) was heated at 125° C.for 5 hours, to afford 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline as asolid (2.212 g, 91%). ¹H NMR (300 MHz, CDCl₃) δ 8.86 (s, 1H), 7.44 (s,1H), 7.34 (s, 1H), 4.34 (t, 4H), 3.89 (t, 4H), 3.50 (s, 3H), 3.49 (s,3H); LC-MS (ESI) m/z 313 (M+H)⁺.

Example 12B Step 1: According to the procedure described in Example 13BStep 1, a mixture of1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A(0.688 g, 2.5 mmol), 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline fromthe previous step (0.782 g, 2.5 mmol), and Cs₂CO₃ (0.977 g, 3 mmol) inisopropanol (15 mL) was heated at 70° C. for 7 hours, to afford1-{3-[6,7-bis(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-(5-tert-butylisoxazol-3-yl)ureaas solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.57 (s, 1H), 8.98 (s, 1H), 8.55(s, 1H), 7.58 (m, 2H), 7.42 (s, 1H), 7.40 (t, 1H), 7.25 (d, 1H), 6.97 (d1H), 6.47 (s, 1H), 4.34 (m, 4H), 3.77 (m, 4H), 3.38 (s, 3H), 3.36 (s,3H), 1.27 (s, 9H).

Example 12B Step 2: The title compound was prepared as described inExample 6B Step 2 using1-{3-[6,7-bis(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-(5-tert-butylisoxazol-3-yl)ureaand 1.0 M HCl/Et₂O solution (2 eq.) in CH₂Cl₂ and MeOH, to afford1-{3-[6,7-bis(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-(5-tert-butylisoxazol-3-yl)ureahydrochloride as a solid (1.169 g, 85%). ¹H NMR (300 MHz, DMSO-d₆) δ9.71 (s, 1H), 9.39 (s, 1H), 8.70 (s, 1H), 7.66 (s, 1H), 7.60 (m, 1H),7.46 (s, 1H), 7.44 (t, 1H), 7.28 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H),4.37 (m, 4H), 3.78 (m, 4H), 3.37 (s, 3H), 3.36 (s, 3H), 1.27 (s, 9H);LC-MS (ESI) m/z 552 (M+H)⁺.

Example 13 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-[3-(6,7-diethoxyquinazolin-4-yloxy)phenyl]ureahydrochloride

Example 13A Step 1: According to the procedure described in Example 6AStep 1, a mixture of ethyl 3,4-dihydroxybenzoate (5.465 g, 30 mmol),bromoethane (7.192 g, 66 mmol), and K₂CO₃ (9.122 g, 66 mmol) in DMF (50mL) was heated at 50° C. for 5 hours, to afford ethyl3,4-diethoxybenzoate as solid (6.439 g, 90%). ¹H NMR (300 MHz, CDCl₃) δ7.65 (dd, 1H), 7.55 (d, 1H), 6.87 (d, 1H), 4.35 (q, 2H), 4.15 (q, 4H),1.48 (m, 6H), 1.38 (t, 3H); LC-MS (ESI) m/z 239 (M+H)⁺.

Example 13A Step 2: According to the procedure described in Example 6AStep 2, to a solution of ethyl 3,4-diethoxybenzoate (6.43 g, 27 mmol) inAcOH (50 mL) was dropped fuming nitric acid (90%, 6.3 g) and thereaction was heated at 50° C. overnight, to afford ethyl4,5-diethoxy-2-nitrobenzoate as a solid (7.175 g, 94%). ¹H NMR (300 MHz,CDCl₃) δ 7.44 (s, 1H), 7.05 (s, 1H), 4.37 (q, 2H), 4.18 (m, 4H), 1.50(m, 6H), 1.35 (t, 3H); LC-MS (ESI) m/z 284 (M+H)⁺.

Example 13A Step 3: According to the procedure described in Example 6AStep 3, a mixture of ethyl 4,5-diethoxy-2-nitrobenzoate (7.17 g, 25.3mmol) and Pd/C (10%, 0.7 g) in EtOAc (150 mL) was stirred under 1atmosphere of hydrogen at room temperature overnight, to afford ethyl2-amino-4,5-diethoxybenzoate as a solid (6.401 g, 99%) ¹H NMR (300 MHz,CDCl₃) δ 7.36 (s, 1H), 6.14 (s, 1H), 5.60 (br, 2H), 4.30 (q, 2H), 4.05(m, 4H), 1.44 (t, 3H), 1.38 (m, 6H); LC-MS (ESI) m/z 254 (M+H)⁺.

Example 13A Step 4: According to the procedure described in Example 6AStep 4, a mixture of ethyl 2-amino-4,5-diethoxybenzoate (2.53 g, 10mmol) and formamidine hydrochloride (0.966 g, 12 mmol) in formamide (10mL) was heated at 140° C. for 5 hours, to afford6,7-diethoxyquinazolin-4(3H)-one as a white solid (1.702 g, 73%). ¹H NMR(300 MHz, CDCl₃) δ 10.49 (br, 1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.14 (s,1H), 4.24 (m, 4H), 1.54 (m, 6H); LC-MS (ESI) m/z 235 (M+H)⁺.

Example 13A Step 5: According to the procedure described in Example 6AStep 5, a mixture of 6,7-diethoxyquinazolin-4(3H)-one (1.70 g, 7.3 mmol)and POCl₃ (3 mL) in toluene (10 mL) was heated at 120° C. for 5 hours toafford 4-chloro-6,7-diethoxyquinazoline as a solid (1.794 g, 98%). ¹HNMR (300 MHz, CDCl₃) δ 8.88 (s, 1H), 7.45 (s, 1H), 7.39 (s, 1H), 4.31(m, 4H), 1.58 (m, 6H); LC-MS (ESI) m/z 253 (M+H)⁺.

Example 13B Step 1: A mixture of1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A(0.137 g, 0.5 mmol), 4-chloro-6,7-diethoxyquinazoline from the previousstep (0.126 g, 0.5 mmol), and Cs₂CO₃ (0.326 g, 1 mmol) in isopropanol (6mL) was heated at 90° C. for 4 hours. The reaction was quenched withwater and extracted with CH₂Cl₂. Extracts were dried over MgSO₄ andconcentrated under reduced pressure. The residue was purified by silicagel chromatography with EtOAc/hexane as eluant to afford1-(5-tert-butylisoxazol-3-yl)-3-[3-(6,7-diethoxyquinazolin-4-yloxy)phenyl]ureaas a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.59 (s, 1H), 9.03 (s, 1H), 8.56(s, 1H), 7.57 (m, 1H), 7.55 (s, 1H), 7.40 (t, 1H), 7.37 (s, 1H), 7.25(d, 1H), 6.96 (dd, 1H), 6.47 (s, 1H), 4.26 (m 4H), 1.43 (m, 6H), 1.27(s, 9H).

Example 13C: The title compound was prepared as described in Example 6BStep 2, using1-(5-tert-butylisoxazol-3-yl)-3-[3-(6,7-diethoxyquinazolin-4-yloxy)phenyl]ureaand 1.0 M HCl/Et₂O solution (2 eq.) in CH₂Cl₂ and MeOH, to afford1-(5-tert-butylisoxazol-3-yl)-3-[3-(6,7-diethoxyquinazolin-4-yloxy)phenyl]ureahydrochloride as a solid (0.053 g, 20%). ¹H NMR (300 MHz, DMSO-d₆) δ9.67 (s, 1H), 9.27 (s, 1H), 8.66 (s, 1H), 7.68 (m, 2H), 7.40 (m, 2H),7.26 (d, 1H), 6.97 (d, 1H), 6.48 (s, 1H), 5.78 (br, 1H), 4.28 (m, 4H),1.43 (m, 6H), 1.27 (s, 9H); LC-MS (ESI) m/z 492 (M+H)⁺.

Example 14 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-[3-(7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-yloxy)phenyl]ureahydrochloride

Example 14A Step 1: According to the procedure described in Example 6AStep 1, a mixture of ethyl 3,4-dihydroxybenzoate (5.465 g, 30 mmol),1,2-dibromoethane (5.636 g, 30 mmol), and K₂CO₃ (6.219 g, 45 mmol) inDMF (100 mL) was heated at 70° C. overnight. The residue was purified bysilica gel chromatography with 20-50% EtOAc/hexane as eluants to affordethyl 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate as an oil (1.423 g,23%). ¹H NMR (300 MHz, CDCl₃) δ 7.58 (d, 1H), 7.56 (dd, 1H), 6.88 (d,1H), 4.30 (m, 6H), 1.37 (t, 3H); LC-MS (ESI) m/z 209 (M+H)⁺.

Example 14A Step 2: According to the procedure described in Example 6AStep 2, to a solution of ethyl2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (1.42 g, 6.8 mmol) andAc₂O (3 mL), in AcOH (15 mL) was dropped fuming nitric acid (1 mL). Thereacted ion was heated at 50° C. for 2 hours, to afford ethyl7-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate as a solid (1.720g, 99%). ¹H NMR (300 MHz, CDCl₃) δ 7.51 (s, 1H), 7.18 (s, 1H), 4.36 (m,6H), 1.33 (t, 3H).

Example 14A Step 3: According to the procedure described in Example 6AStep 3 a mixture of ethyl7-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (1.72 g, 6.8 mmol)and Pd/C (10%, 0.2 g) in EtOAc (100 mL) was stirred under 1 atmosphereof hydrogen at room temperature overnight, to afford ethyl7-amino-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate as a solid (1.459g, 96%). ¹H NMR (300 MHz, CDCl₃) δ 7.41 (s, 1H), 6.18 (s, 1H), 5.41 (br,2H), 4.30 (m, 4H), 4.19 (q, 2H), 1.38 (t, 3H); LC-MS (ESI) m/z 224(M+H)⁺.

Example 14A Step 4: According to the procedure described in Example 6AStep 4, a mixture of ethyl7-amino-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (1.45 g, 6.5 mmol)and formamidine hydrochloride (1.208 g, 15 mmol) in formamide (20 mL)was heated at 130° C. for 8 hours, to afford7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4(3H)-one as a solid (1.114 g,84%). ¹H NMR (300 MHz, CDCl₃ and drops DMSO-d₆) δ 11.80 (br, 1H), 7.88(s, 1H), 7.63 (s, 1H), 7.13 (s, 1H), 4.36 (m, 4H); LC-MS (ESI) m/z 205(M+H)⁺.

Example 14A Step 5: According to the procedure described in Example 6AStep 5, a mixture of 7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4(3H)-one(1.114 g, 5.46 mmol) and POCl₃ (10 mL) in toluene (10 mL) was heated at125° C. for 5 hours to afford4-chloro-7,8-dihydro-[1,4]dioxino[2,3-g]quinazoline as a solid (1.143 g,94%). ¹H NMR (300 MHz, CDCl₃) δ 8.90 (s, 1H), 7.70 (s, 1H), 7.65 (s,1H), 4.46 (m, 4H).

Example 14B: According to the procedure described in Example 13B Step 1,a mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea fromExample 1A (0.138 g, 0.5 mmol),4-chloro-7,8-dihydro-[1,4]dioxino[2,3-g]quinazoline from the previousstep (0.111 g, 0.5 mmol), and Cs₂CO₃ (0.326 g, 1 mmol) in isopropanol (7mL) was heated at 70° C. for 13 hours, to afford1-(5-tert-butylisoxazol-3-yl)-3-[3-(7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-yloxy]phenyl)ureaas a solid. ¹H NMR (300 MHz, CDCl₃) δ 9.3 (br, 1H), 9.10 (s, 1H), 8.59(s, 1H), 7.72 (s, 1H), 7.60 (m, 1H), 7.42 (s, 1H), 7.31 (m, 2H), 6.95(d, 1H), 6.02 (s, 1H), 4.41 (m 4H), 1.30 (s, 9H).

Example 14C: According to the procedure described in Example 6B Step 2,to a solution of1-(5-tert-butylisoxazol-3-yl)-3-[3-(7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-yloxy)phenyl]ureain CH₂Cl₂ and MeOH was added 1.0 M HCl/Et₂O solution to afford1-(5-tert-butylisoxazol-3-yl)-3-[3-(7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-yloxy)phenyl]ureahydrochloride as a solid (0.086 g, 35%). ¹H NMR (300 MHz, DMSO-d₆) δ9.67 (s, 1H), 9.28 (s, 1H), 8.63 (s, 1H), 7.72 (s, 1H), 7.57 (m, 1H),7.43 (s, 1H), 7.40 (t, 1H), 7.28 (d, 1H), 6.96 (d, 1H), 6.48 (s, 1H),5.43 (br, 1H), 4.47 (m, 4H), 1.28 (s, 9H); LC-MS (ESI) m/z 462 (M+H)⁺.

Example 15 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-{3-[7-methoxy-6-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}ureahydrochloride

Example 15A Step 1: According to the procedure described in Example 6AStep 1, a mixture of methyl 3-hydroxy-4-methoxybenzoate (5.00 g, 27.4mmol), 1-bromo-2-methoxyethane (4.96 g, 35.7 mmol), and K₂CO₃ (4.6 g,32.9 mmol) in DMF (20 mL) was heated at 90° C. overnight, to affordmethyl 4-methoxy-3-(2-methoxyethoxy)benzoate as a solid (5.6 g, 85%). ¹HNMR (300 MHz, DMSO-d₆) δ 7.60 (dd, 1H), 7.46 (d, 1H), 7.09 (d, 1H), 4.12(m, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.67 (m, 2H), 3.33 (s, 3H).

Example 15A Step 2. According to the procedure described in Example 6AStep 2, to a solution of methyl 4-methoxy-3-(2-methoxyethoxy)benzoate(5.6 g, 23.3 mmol) and Ac₂O (12 mL) in AcOH (60 mL) was dropped fumingnitric acid (90%, 4 mL). The reaction was heated at 50° C. for 3 hours,and the residue was purified by silica gel chromatography with 0-15%EtOAc/hexane as eluants to afford methyl4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate as a solid (3.67 g, 56%).¹H NMR (300 MHz, DMSO-d₆) δ 7.64 (s, 1H), 7.34 (s, 1H), 4.26 (m, 2H),3.91 (s, 3H), 3.82 (s, 3H), 3.68 (m, 2H), 3.33 (s, 3H).

Example 15A Step 3. According to the procedure described in Example 6AStep 3, a mixture of methyl4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate (3.67 g, 12.9 mmol) andPd/C (10%, 0.4 g) in EtOAc (60 mL) was stirred under 1 atmosphere ofhydrogen at room temperature overnight, to afford methyl2-amino-4-methoxy-5-(2-methoxyethoxy)benzoate as a solid (3.05 g, 93%).¹H NMR (300 MHz, DMSO-d₆) δ 7.15 (s, 1H), 6.46 (s, 2H), 6.36 (s, 1H),3.91 (m, 2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.59 (m, 2H), 3.32 (s, 3H).

Example 15A Step 4. According to the procedure described in Example 6AStep 4, a mixture of methyl2-amino-4-methoxy-5-(2-methoxyethoxy)benzoate (3.05 g, 11.9 mmol) andAcOH (5.4 mL) in formamide (15.25 mL) was heated at 140° C. overnight,to afford 7-methoxy-6-(2-methoxyethoxy)quinazolin-4(3H)-one as a solid(2.07 g, 69%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.0 (br, 1H), 7.99 (s, 1H),7.45 (s, 1H), 7.14 (s, 1H), 4.19 (t, 2H), 3.91 (s, 3H), 3.71 (t, 2H),3.32 (s, 3H).

Example 15A Step 5. According to the procedure described in Example 6AStep 5, a mixture of 7-methoxy-6-(2-methoxyethoxy)quinazolin-4(3H)-one(0.6 g, 2.4 mmol) and POCl₃ (1 mL) in toluene (10 mL) was heated at 125°C. for 2 hours, to afford4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline as solid (0.445 g,69%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.88 (s, 1H), 7.45 (s, 1H), 7.41 (s,1H), 4.33 (t, 2H), 4.03 (s, 3H), 3.77 (t, 2H), 3.33 (s, 3H).

Example 15B: According to the procedure described in Example 50, amixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (0.201g, 0.73 mmol) from Example 1A,4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline (0.195 g, 0.73 mmol)from the previous step, and Cs₂CO₃ (0.261 g, 0.8 mmol) in isopropanol(10 mL) was heated at 70° C. for 7 hours, to afford1-(5-tert-butylisoxazol-3-yl)-3-{3-[7-methoxy-6-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}ureaas a solid. ¹H NMR (300 MHz, CDCl₃) δ 9.13 (br and s, 2H), 8.61 (s, 1H),7.62 (s, 1H), 7.55 (s, 1H), 7.31 (m, 3H), 6.97 (dd, 1H), 6.08 (s, 1H),4.34 (t, 2H), 4.11 (s, 3H), 3.89 (t, 2H), 3.49 (s, 3H), 1.30 (s, 9H);LC-MS (ESI) m/z 508 (M+H)⁺.

Example 15C: The title compound was prepared as described in Example 6BStep 2 using1-(5-tert-butylisoxazol-3-yl)-3-{3-[7-methoxy-6-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}ureaand 1.0 M HCl in Et₂O solution (1 mL) in CH₂Cl₂ and MeOH, to afford1-(5-tert-butylisoxazol-3-yl)-3-{3-[7-methoxy-6-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}ureahydrochloride as a solid (0.211 g, 53%). ¹H NMR (300 MHz, DMSO-d₆) δ9.68 (s, 1H), 9.33 (s, 1H), 8.68 (s, 1H), 7.63 (s, 1H), 7.60 (d, 1H),7.43 (s, 1H), 7.41 (t, 1H), 7.27 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H),5.36 (br, 1H), 4.34 (m, 2H), 4.02 (s, 3H), 3.77 (m, 2H), 3.34 (s, 3H),1.27 (s, 9H); LC-MS (ESI) m/z 508 (M+H)⁺.

Example 16 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(piperidin-1-yl)ethoxy)quinazolin-4-yloxy)phenyl)urea

Example 16A Step 1: To DMF (40 mL) was added potassium carbonate (9.1 g,65.9 mmol) and methyl 3-hydroxy-4-methoxybenzoate (10.0 g, 54.9 mmol)and the mixture stirred 30 minutes at room temperature1-bromo-2-chloroethane (11.0 g, 76.8 mmol) was added and the mixture washeated at 60° C. overnight at which point excess 1-bromo-2-chloroethane(5.5 g, 38.4 mmol) was added and heating continued for 8 hours. Aftercooling to room temperature, the mixture was diluted with H₂O, filtered,and the solid washed with EtOAc to give methyl3-(2-chloroethoxy)-4-methoxybenzoate (4.04 g, 16.6 mmol, 30%). ¹H NMR(300 MHz, DMSO-d₆) δ 7.63 (d, 1H), 7.47 (s, 1H), 7.11 (d, 1H), 4.29 (t,2H), 3.95 (t, 2H), 3.86 (s, 3H), 3.81 (s, 3H); LC-MS (ESI) m/z 245(M+H)⁺.

Example 16A Step 2: To acetic acid (42 mL) and acetic anhydride (8.5 mL)was added methyl 3-(2-chloroethoxy)-4-methoxybenzoate (4.0 g, 16.3 mmol)followed by 70% nitric acid (2.8 mL) and the mixture heated at 50° C.for 1 hour. The mixture was poured into H₂O, filtered, and washed withH₂O to give methyl 5-(2-chloroethoxy)-4-methoxy-2-nitrobenzoate (4.08 g,14.1 mmol, 86%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.67 (s, 1H), 7.38 (s, 1H),4.43 (t, 2H), 3.99 (t, 2H), 3.94 (s, 3H), 3.85 (s, 3H).

Example 16A Step 3: To methyl5-(2-chloroethoxy)-4-methoxy-2-nitrobenzoate (4.07 g, 14.1 mmol) underargon was added 10% palladium on carbon and in EtOAc (150 mL) and MeOH(50 mL). The flask was flushed with H₂ (g) and stirred under H₂ (1 atm)for 30 minutes. The mixture was filtered through Celite and concentratedin vacuo to give methyl 2-amino-5-(2-chloroethoxy)-4-methoxybenzoate(3.61 g, 13.9 mmol, 99%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.20 (s, 1H), 6.52(br s, 2H), 6.38 (s, 1H), 4.07 (t, 2H), 3.85 (t, 2H), 3.77 (s, 3H), 3.75(s, 3H); LC-MS (ESI) m/z 260 (M+H)⁺.

Example 16A Step 4: To a solution of methyl2-amino-5-(2-chloroethoxy)-4-methoxybenzoate (3.61 g, 13.9 mmol) inethanol was added formamidine hydrochloride and the mixture heated in asealed tube at 130° C. overnight. The reaction was cooled to roomtemperature and filtered to give6-(2-chloroethoxy)-4-hydroxy-7-methoxyquinazoline (3.05 g, 12.0 mmol,86%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.09 (br s, 1H), 8.00 (s, 1H), 7.47(s, 1H), 7.16 (s, 1H), 4.36 (t, 2H), 4.00 (t, 2H), 3.92 (s, 3H); LC-MS(ESI) m/z 255 (M+H)⁺.

Example 16B: The intermediate6-(2-chloroethoxy)-4-hydroxy-7-methoxyquinazoline from the previous step(5.0 g, 19.6 mmol) was reacted according to the procedure described inExample 4A Step 2 to give4-chloro-6-(2-chloroethoxy)-7-methoxyquinazoline (4.3 g, 15.8 mmol,80%). LC-MS (ESI) m/z 273 (M+H)⁺.

Example 16C: To a slurry of cesium carbonate in THF was added1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A(2.02 g, 7.3 mmol). After stirring for about 15 minutes at roomtemperature, the chloride intermediate (2.0 g, 7.3 mmol) from theprevious step was added and the reaction mixture was heated at 50° C.overnight. The mixture was diluted with EtOAc and washed with water andbrine, dried over MgSO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by column chromatography (10-50% EtOAc/hexanes) togive1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea(2.15 g, 4.2 mmol, 58%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s, 1H), 9.00(s, 1H), 8.58 (s, 1H), 7.61 (s, 2H), 7.48-7.37 (m, 2H), 7.26 (d, 1H),6.98 (d, 1H), 6.49 (s, 1H), 4.53-4.47 (m, 2H), 4.12-4.00 (m, 5H), 1.29(s, 9H); LC-MS (ESI) m/z 512 (M+H)⁺.

Example 16D.1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea(200 mg, 0.39 mmol) from the previous step was treated with piperidine(0.116 mL, 1.17 mmol), tetrabutylammonium iodide

(0.39 mmol) and N,N′-diisopropylethylamine (0.78 mmol) inN,N′-dimethylformamide. The mixture was heated to 60° C. for 56 h andcooled to room temperature. Water was added and the solid filtered offand dried. The crude solid was purified by preparative HPLC (phenylhexylreverse phase column) and the obtained solid triturated with water (10mL) and drops of methanol, then filtered off and dried under high vacuumto afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(piperidin-1-yl)ethoxy)quinazolin-4-yloxy)phenyl)ureaas a colorless solid (29 mg, 13%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.80(brs, 1H), 9.10 (brs, 1H), 8.55 (s, 1H), 7.64 (s, 1H), 7.59 (s, 1H),7.37-7.42 (m, 2H), 7.26 (m, 1H), 6.96 (m, 1H), 6.48 (s, 1H), 4.26-4.30(m, 2H), 3.99 (s, 3H), 2.72-2.76 (m, 2H), 2.40-2.50 (m, 4H), 1.48-1.52(m, 4H), 1.37-1.39 (m, 2H), 1.30 (s, 9H); LC-MS (ESI) m/z 561 (M+H)⁺.

Example 17 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea

1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea(200 mg, 0.39 mmol) from Example 16C was reacted with4-piperidinemethanol (135 mg, 1.17 mmol) according to the proceduredescribed in Example 16D to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)ureaas a colorless solid (36 mg, 16%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.70(brs, 1H), 9.10 (brs, 1H), 8.55 (s, 1H), 7.63 (s, 1H), 7.58 (s, 1H),7.37-7.43 (m, 2H), 7.27 (m, 1H), 6.97 (m, 1H), 6.48 (s, 1H), 4.20-4.50(m, 3H), 3.99 (s, 3H), 3.23 (m, 2H), 2.96-3.00 (m, 2H), 2.74-2.78 (m,2H), 2.01-2.05 (m, 2H), 1.61-1.65 (m, 2H), 1.27 (s, 9H), 1.00-1.15 (m,2H); LC-MS (ESI) m/z 591 (M+H)⁺.

Example 18 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-yloxy)phenyl)urea

1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea(200 mg, 0.39 mmol) from Example 16C was reacted with N-methylpiperazine (0.130 mL, 1.17 mmol) according to the procedure describedfor Example 16D to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-yloxy)phenyl)ureaas a colorless solid (18 mg, 8%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (brs,1H), 9.00 (brs, 1H), 8.55 (s, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.37-7.42(m, 2H), 7.25 (m, 1H), 6.96 (m, 1H), 6.47 (s, 1H), 4.26-4.30 (m, 2H),3.99 (s, 3H), 2.75-2.79 (m, 2H), 2.20-2.50 (m, 8H), 2.13 (s, 3H), 1.27(s, 9H); LC-MS (ESI) m/z 576 (M+H)⁺.

Example 19 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea

Prepared from1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea(200 mg, 0.39 mmol) from Example 16C (200 mg, 0.39 mmol) and1-(2-hydroxyethyl)piperazine (0.144 mL, 1.17 mmol) according to theprocedure described for Example 16D to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)ureaas a colorless solid (28 mg, 12%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.59(brs, 1H), 9.01 (brs, 1H), 8.55 (s, 1H), 7.63 (s, 1H), 7.58 (s, 1H),7.37-7.42 (m, 2H), 7.26 (m, 1H), 6.96 (m, 1H), 6.47 (s, 1H), 4.26-4.35(m, 3H), 3.99 (s, 3H), 3.40-3.50 (m, 2H), 2.75-2.79 (m, 2H), 2.30-2.50(m, 9H), 1.27 (s, 9H); LC-MS (ESI) m/z 606 (M+H)⁺.

Example 20 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)urea

Prepared from 145-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (200 mg, 0.39 mmol) fromExample 16C (200 mg, 0.39 mmol) and morpholine (0.102 mL, 1.17 mmol)according to the procedure described for Example 16D to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)ureaas a colorless solid (28 mg, 13%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.60(brs, 1H), 9.08 (brs, 1H), 8.56 (s, 1H), 7.58-7.65 (m, 2H), 7.38-7.43(m, 2H), 7.25 (m, 1H), 6.97 (m, 1H), 6.48 (s, 1H), 4.30-4.32 (m, 2H),4.00 (s, 3H), 3.60-3.62 (m, 4H), 2.80 (m, 2H), 2.49-2.52 (m, 4H), 1.27(s, 9H); LC-MS (ESI) m/z 563 (M+H)⁺.

Example 21 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)urea

Example 21A Step 1: To DMF (80 mL) was added potassium carbonate (5.7 g,41.1 mmol) and methyl 3-hydroxy-4-methoxybenzoate (5.0 g, 27.4 mmol).The mixture was cooled to 0° C. and 1-bromo-3-chloropropane (8.64 g,57.9 mmol) in DMF (10 mL) was added dropwise over 30 minutes. Themixture was allowed to warm to r.t overnight. After removing most of theDMF in vacuo, the remaining oil was diluted with H₂O and filtered togive methyl 3-(3-chloropropoxy)-4-methoxybenzoate (6.65 g, 25.8 mmol,94%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.61 (d, 1H), 7.47 (s, 1H), 7.09 (d,1H), 4.12 (t, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.78 (t, 2H), 2.23-2.15(m, 2H); LC-MS (ESI) m/z 259 (M+H)⁺.

Example 21A Step 2: Methyl 3-(3-chloropropoxy)-4-methoxybenzoate (6.65g, 25.7 mmol) was reacted with nitric acid as described in Example 16AStep 2 to give methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate(6.70 g, 22.1 mmol, 86%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.65 (s, 1H), 7.37(s, 1H), 4.26 (t, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 3.76 (t, 2H),2.26-2.18 (m, 2H).

Example 21A Step 3: Methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate(6.70 g, 22.1 mmol) in EtOAc (100 mL) was reacted with H₂ in thepresence of 10% palladium on carbon in the manner described in Example16A Step 3 to give methyl 2-amino-5-(3-chloropropoxy)-4-methoxybenzoate(6.0 g, 22.0 mmol, 99%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.18 (s, 1H), 6.49(br s, 2H), 6.37 (s, 1H), 3.93 (t, 2H), 3.82-3.71 (m, 8H), 2.14-2.06 (m,2H); LC-MS (ESI) m/z 274 (M+H)⁺.

Example 21A Step 4: Methyl 2-amino-5-(3-chloropropoxy)-4-methoxybenzoate(6.0 g, 21.9 mmol) in EtOAc was reacted with formamidine hydrochloridein the manner described in Example 16A Step 4 to give6-(3-chloropropoxy)-4-hydroxy-7-methoxyquinazoline (4.48 g, 16.7 mmol,76%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (br s, 1H), 8.00 (s, 1H), 7.47(s, 1H), 7.15 (s, 1H), 4.19 (t, 2H), 3.97 (s, 3H), 3.81 (t, 2H),2.27-2.19 (m, 2H); LC-MS (ESI) m/z 269 (M+H)⁺.

Example 21A Step 5: The intermediate6-(3-chloropropoxy)-4-hydroxy-7-methoxyquinazoline (3.5 g, 13.0 mmol)was reacted with POCl₃ in the manner described in Example 4A Step 2 togive 4-chloro-6-(3-chloropropoxy)-7-methoxyquinazoline (3.2 g, 11.2mmol, 86%). LC-MS (ESI) m/z 287 (M+H)⁺.

Example 21B: 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea fromExample 1A (1.92 g, 6.97 mmol) and4-chloro-6-(3-chloropropoxy)-7-methoxyquinazoline from the previous step(2.0 g, 6.97 mmol) were reacted in the manner described in Example 16Cto give1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea(2.00 g, 3.8 mmol, 55%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.56 (s, 1H), 8.98(s, 1H), 8.54 (s, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.38 (t, 1H), 7.33(s, 1H), 7.26 (d, 1H), 6.96 (d, 1H), 6.47 (s, 1H), 4.27 (t, 2H), 3.98(s, 3H), 3.82 (t, 2H), 2.30-2.24 (m, 2H), 1.29 (s, 9H); LC-MS (ESI) m/z526 (M+H)⁺.

Example 21C: In a sealed reaction flask1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea(200 mg, 0.38 mmol) was dissolved in 3 mL of anhydrous DMF, to thissolution tetrabutylammonium iodide (140 mg, 0.38 mmol) was addedfollowed by N-methylpiperazine (0.127 mL, 1.14 mmol) and the reactionheated at 60° C. for 56 hours. At the end of this time 10 mL of waterwas added and the resulting solid removed by filtration. The solid waspurified by reversed phase HPLC using a phenyl-hexyl reverse phasecolumn with a 30-50% ACN/H₂O gradient over 60 minutes. The appropriatepeak was concentrated, basified with saturated sodium bicarbonate andextracted twice with ethyl acetate. The extracts were dried withmagnesium sulfate, filtered and concentrated to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)ureaas a solid weighing 15.75 mg. ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s, 1H),9.00 (s, 1H), 8.55 (s, 1H), 7.58 (d, 2H), 7.4 (m, 2H), 7.26 (m, 1H),6.98 (m, 1H), 6.47 (s, 1H), 4.2 (m, 2H), 3.99 (s, 3H), 2.5-2.2 (m, 9H),2.11 (s, 3H), 1.99 (m, 2H), 1.27 (s, 9H). LC-MS (ESI) m/z 590 (M+H)⁺.

Example 22 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-yloxy)phenyl)urea

In the manner described in Example 21C,1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea(200 mg, 0.38 mmol) from Example 21B was reacted with morpholine (99 μL,1.14 mmol), diisopropylethyl amine (199 μL, 1.14 mmol), and tetrabutylammonium iodide (140 mg, 0.38 mmol). After heating at 60° C. overnightthe reaction was cooled to room temperature, and 10 mL of water added.The resulting precipitate was collected by filtration and purified byHPLC on a phenyl-hexyl reverse phase column eluting with anacetonitrile/water gradient 35-55% over 60 minutes. The major peak wascollected, neutralized to pH-8 with saturated sodium bicarbonate andextracted twice with ethyl acetate. The extracts were combined, driedwith magnesium sulfate, and concentrated to a solid. The solid wastriturated with 20:1 methanol water and the solid removed by filtrationand dried to give 72 mg of the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ 9.57 (s, 1H), 8.99 (s, 1H), 8.55 (s, 1H), 7.58 (m, 2H), 7.39 (m, 2H),7.26 (m, 1H), 6.99 (m, 1H), 6.47 (s, 1H), 4.25 (m, 2H), 3.99 (s, 3H),3.58 (m, 4H), 2.5-2.35 (m, 6H), 1.97 (m, 2H), 1.30 (s, 9H). LC-MS (ESI)m/z 577 (M+H)⁺.

Example 23 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(piperidin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)urea

The title compound was prepared using the procedure for Example 21C,substituting piperidine (0.113 mL, 1.14 mmol) for theN-methylpiperazine. The title compound (38.76 mg) was isolated. ¹H NMR(300 MHz, DMSO-d₆) δ 9.64 (s, 1H), 9.07 (s, 1H), 8.55 (s, 1H), 7.58 (d,2H), 7.40 (m, 2H), 7.25 (m, 1H), 6.98 (m, 1H), 6.48 (s, 1H), 4.23 (m,2H), 4.00 (s, 3H), 2.4-2.2 (m, 6H), 2.0 (m, 2H), 1.5 (m, 4H), 1.3 (m,11H). LC-MS (ESI) m/z 575 (M+H)⁺.

Example 24 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea

The title compound was prepared using the procedure for Example 21Csubstituting 4-piperidinemethanol (131 mg, 1.14 mmol) for the N-methylpiperazine. Purification was carried out under identical conditions. Thetitle compound (27.3 mg) was isolated. ¹H NMR (300 MHz, DMSO-d₆) δ 9.58(s, 1H), 9.00 (s, 1H), 8.55 (s, 1H), 7.57 (d, 2H), 7.38 (m, 2H), 7.27(m, 1H), 6.95 (m, 1H), 6.47 (s, 1H), 4.39 (m, 1H), 4.2 (m, 2H), 3.95 (s,3H), 3.20 (m, 2H), 2.90 (m, 2H), 2.49 (m, 2H), 2.1-1.8 (m, 4H), 1.6 (m,2H), 1.3 (s, 9H), 1.2 (m, 2H); LC-MS (ESI) m/z 605 (M+H)⁺.

Example 25 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(4-(methylsulfonyl)piperazin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)urea

The title compound was prepared using the procedure for Example 21C,substituting 1-methylsulfonyl piperazine (182 mg, 1.14 mmol) for theN-methyl piperazine. Purification was carried out under identicalconditions. The title compound (52.69 mg) was isolated. ¹H NMR (300 MHz,DMSO-d₆) δ 9.7 (s, 1H), 9.1 (s, 1H), 8.55 (s, 1H), 7.58 (d, 2H), 7.37(m, 2H), 7.23 (m, 1H), 6.97 (m, 1H), 6.47 (s, 1H), 4.23 (m, 2H), 4.00(s, 3H), 3.10 (m, 4H), 2.82 (s, 3H), 2.00 (m, 2H), 1.37 (s, 9H). LC-MS(ESI) m/z 654 (M+H)⁺.

Example 26 Preparation of1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-7-methoxy-quinazolin-4-yloxy}-phenyl)-urea

The intermediate1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea(200 mg, 0.38 mmol) from Example 21B was treated withthiomorpholine-1,1-dioxide (154 mg, 1.14 mmol), tetrabutylammoniumiodide (140 mg, 0.38 mmol) and N,N′-diisopropylethylamine (135 μL, 0.76mmol) in N,N′-dimethylformamide (2 mL). The mixture was heated to 60° C.for 56 h and cooled to room temperature. Water was added and the solidfiltered off and dried. The crude solid was purified by preparative HPLC(Phenomenex phenylhexyl reverse phase column) and the obtained solidtriturated with water and drops of methanol, then filtered off and driedunder high vacuum to afford1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-7-methoxy-quinazolin-4-yloxy}-phenyl)-urea(46.40 mg, 20%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.62 (bs, 1H),9.04 (bs, 1H), 8.56 (s, 1H), 7.57 (d, 2H), 7.40-7.37 (m, 2H), 7.25 (d,1H), 6.97 (d, 1H), 6.47 (s, 1H), 4.25-4.21 (m, 2H), 4.00 (s, 3H), 3.34(bs, 4H), 2.93 (bs, 4H), 2.68-2.64 (m, 2H), 1.99-1.96 (m, 2H), 1.18 (s,9H); LC-MS (ESI) m/z 625 (M+H)⁺.

Example 27 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yloxy)phenyl)urea

Example 27A Step 1: To a solution of4-(3-chloro-propoxy)-3-methoxy-benzoic acid methyl ester (12 g, 65.8mmol) and potassium carbonate (36.3 g, 263 mmol) in DMF (100 mL) wasadded 1-bromo-3-chloro-propane (32.5 mL, 329 mmol). The mixture wasstirred at ambient temperature for 15 hours. Completion of the reactionwas monitored by TLC. The reaction mixture was diluted with ethylacetate and the ethyl acetate layer was washed with water and brine. Theorganic layer was dried (Na₂SO₄) and concentrated to afford4-(3-chloropropoxy)-3-methoxy-benzoic acid methyl ester (15 g, 88%) as awhite solid. ¹H NMR (300 MHz, CDCl₃) δ 7.65 (d, 1H), 7.52 (s, 1H), 6.88(d, 1H), 4.20 (t, 2H), 3.90 (s, 6H), 3.75 (t, 2H), 2.30 (q, 2H).

Example 27A Step 2: The intermediate from Step 1 (26.4 g, 102 mmol) wastaken in acetic acid (185 mL) and acetic anhydride (15 mL) was added.The solution was cooled to 0° C. and 90% nitric acid (15 mL) was added.The reaction mixture was stirred for 10-15 minutes at ambienttemperature, then heated to 50° C. for 3 hours. Completion of thereaction was monitored by LCMS. The reaction mixture was cooled and wasdiluted with ethyl acetate. The ethyl acetate layer was washed with aq.sodium bicarbonate, and concentrated to afford the pure compound4-(3-chloro-propoxy)-5-methoxy-2-nitro-benzoic acid methyl ester (29.14g, 94%) yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.68 (s, 1H), 7.33 (s,1H), 4.24 (t, 2H), 3.92 (s, 3H), 3.82 (s, 3H), 3.77 (t, 2H), 2.21 (q,2H).

Example 27A Step 3: To a solution of the intermediate from Step 2 (29.14g, 95.8 mmol) in ethyl acetate:methanol (3:1, 1 L) was added 10% Pd/C (3g). The mixture was stirred under H₂ for 12 hours. Completion of thereaction was monitored by LCMS. The reaction mixture was filtered usinga celite pad and washed with excess ethyl acetate. The filtrate wasevaporated to dryness to afford the pure2-amino-4-(3-chloro-propoxy)-5-methoxy-benzoic acid methyl ester (24.2g, 94%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.13 (s, 1H), 6.43 (s,2H), 6.39 (s, 1H), 4.04 (t, 2H), 3.80 (t, 2H), 3.74 s, 3H), 3.65 (s,3H), 2.19 (m, 2H), LC-MS (ESI)m/z 274 (M+H)⁺.

Example 27A Step 4: To a solution of the intermediate from Step 3 (4.2g, 15.35 mmol) in ethanol was added formamidine hydrochloride (2.97 g,36.96 mmol). The mixture was heated at 140° C. in sealed tube for 12 h.Completion of the reaction was monitored by LCMS. The precipitate formedwas filtered and washed with ethanol and dried to afford the purecompound 7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ol (2.32 g, 56%) asa yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 11.93 (brs, 1H), 7.99 (s,1H), 7.45 (s, 1H), 7.16 (s, 1H), 4.23 (t, 2H), 3.88 (s, 3H), 3.80 (t,2H), 2.23 (t, 2H), LC-MS (ESI)m/z 269 (M+H)⁺.

Example 27A Step 5: To a solution of the intermediate from Step 4 (3.00g, 11.16 mmol) in toluene (30 mL) in a pressure vessel was addedphosphorous oxychloride (8 mL). The mixture was heated to 125° C. for 5hours. Completion of the reaction was monitored by LCMS. The mixture wasconcentrated to dryness and excess ethyl acetate was added. The solutionwas washed with water and brine and was dried (Na₂SO₄) and concentratedto afford the pure compound4-chloro-7-(3-chloro-propoxy)-6-methoxy-quinazoline (2.51 g, 78%) as ayellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.85 (s, 1H), 7.48 (s, 1H),7.35 (s, 1H), 4.35 (t, 2H), 4.00 (s, 3H), 3.75 (t, 2H), 2.25 (q, 2H).LC-MS (ESI)m/z 287 (M+H)⁺.

Example 27B: To a solution of(1-(5-tert-butyl-isoxazol-3-yl)-3-(3-hydroxy-phenyl)-urea, 300 mg, 1.089mmol) from Example 1A and(4-chloro-7-(3-chloro-propoxy)-6-methoxy-quinazoline (343.96 mg, 1.119mmol), from the previous step in THF, was added Cs₂CO₃ (532.2 mg, 1.63mmol) and the mixture was heated at 50° C. for 12 hours. Completion ofthe reaction was monitored by LCMS. The reaction mixture was dilutedwith ethyl acetate and the ethyl acetate layer was washed with water andbrine successively. The organic layer was dried (Na₂SO₄) andconcentrated to dryness. The crude compound was purified by columnchromatography to afford the pure compound1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea,(310 mg, 61%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.55 (s,1H), 9.00 (s, 1H), 8.55 (s, 1H), 7.55 (m, 2H), 7.40 (m, 2H), 7.25 (d,1H), 6.95 (d, 1H), 6.45 (s, 1H), 4.35 (t, 2H), 4.00 (s, 3H), 3.85 (2,2H), 1.30 (s, 9H); LC-MS (ESI)m/z 526 (M+H)⁺.

Example 27C: In a sealed reactor(1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-ureafrom the previous step (300 mg, 0.57 mmol) was dissolved in 10 mL of dryDMF. To this solution was added diisopropylethyl amine (220 mg, 1.7mmol), tetrabutylammonium iodide (210 mg, 0.57 mmol) and morpholine (149mg, 1.7 mmol). The reaction was heated to 60° C. for 48 hours. Thesolution was then poured into 100 mL of water and extracted three timeswith ethyl acetate, the extracts combined, washed with brine, dried withmagnesium sulfate, filtered and concentrated. The resulting oil waspurified using silica gel chromatography eluting with amethanol/dichloromethane gradient 1-12% over 18 column volumes. Theappropriate peak was concentrated, then dissolved in 13 mL ofdichloromethane. To this was added 3 mL of 1M HCl in ether and thesolution concentrated to a solid. The solid was dissolved in a minimalamount of methanol and the salt precipitated by adding ether. Theresulting precipitate was collected by vacuum filtration to afford thetitle compound (264 mg). ¹H NMR (300 MHz, DMSO-d₆) δ 10.7 (s, 1H), 9.76(s, 1H), 9.56 (s, 1H), 8.66 (s, 1H), 7.62 (m, 2H), 7.5-7.3 (m, 2H), 7.28(m, 1H), 6.95 (m, 1H), 6.48 (s, 1H), 4.36 (m, 2H), 4.04 (s, 6H), 3.54(m, 4H), 3.30 (m, 3H), 3.2 (m, 2H), 2.3 (m, 3H), 1.30 (s, 9H). LCMS(ESI) m/z 577 (M+H)

Example 28 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)urea

To a solution of(1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea(225 mg, 0.427 mmol) from Example 27B in DMF (3 mL) was added N-methylpiperazine (0.142 mL, 1.281 mmol) followed by diisopropyl ethylamine(0.223 mL, 1.281 mmol) and tetrabutyl ammonium iodide (157.72 mg, 0.427mmol). The reaction mixture was heated at 60° C. for 15 h. Formation ofthe product was determined by LCMS. The crude reaction mixture waspurified by preparative HPLC (using a phenyl-hexyl reverse phase columneluted with gradient of solvent A=0.05% HOAc/H₂O and solvent B=0.05%HOAc/CH₃CN). The appropriate fractions were concentrated followed bytrituration with ether to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)urea(46 mg, 18%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.68 (s, 1H),9.25 (s, 1H), 8.55 (s, 1H), 7.60 (d, 2H), 7.40 (m, 2H), 7.25 (d, 1H),6.95 (d, 1H), 6.50 (s, 1H), 4.25 (m, 2H), 3.98 (s, 3H), 2.55-2.30 (m,10H), 2.15 (s, 3H), 1.98 (m, 2H), 1.28 (s, 9H); LC-MS (ESI)m/z 590(M+H)⁺.

Example 29 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-hydroxymethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea

In the manner described in Example 28(1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea(225 mg, 0.427 mmol) from Example 27B was reacted withpiperidin-4-yl-methanol (147 mg, 1.281 mmol) to yield1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-hydroxymethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea (86 mg,33%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.60 (s, 1H), 9.05(s, 1H), 8.55 (s, 1H), 7.55 (d, 2H), 7.35 (m, 2H), 7.25 (d, 1H), 6.95(d, 1H), 6.45 (s, 1H), 4.40 (m, 1H), 4.22 (m, 2H), 4.00 (s, 3H), 3.22(m, 2H), 2.80 (d, 2H), 2.45 (m, 2H), 2.10-1.85 (m, 4H), 1.65 (d, 2H),1.30 (s, 10H), 1.15 (m 2H); LC-MS (ESI)m/z 605 (M+H)⁺.

Example 30 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea

To a solution of(1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-ureafrom Example 27B (225 mg, 0.427 mmol) in DMF (3 mL) was added2-piperazin-1-yl-ethanol (0.157 mL, 1.281 mmol) followed bydiisopropylethylamine (0.223 mL, 1.281 mmol) and tetrabutylammoniumiodide (157.72 mg, 0.427 mmol). The reaction mixture was heated at 60°C. for 2 days. Formation of the product was determined by LCMS. Thecrude reaction mixture was purified by preparative HPLC (usingphenyl-hexyl reverse phase column eluted with gradient of solventA=0.05% HOAc/H₂O and solvent B=0.05% HOAc/CH₃CN) to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea(68 mg, 26%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.45 (brs,2H), 8.55 (s, 1H), 7.55 (d, 2H), 7.35 (d, 2H), 7.25 (d, 1H), 6.85 (d,1H), 6.45 (s, 1H), 4.20 (m, 2H), 3.88 (s, 3H), 3.45 (m, 2H), 2.50-2.25(m, 12H), 2.00 (m, 2H), 1.25 (s, 9H); LC-MS (ESI)m/z 620 (M+H)⁺.

Example 31 Preparation of1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{7-[3-(3-hydroxy-pyrrolidin-1-yl)-propoxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-urea

In the manner described in Example 28(1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea(225 mg, 0.427 mmol) from Example 27B was reacted with pyrrolidin-3-ol(0.103 mL, 1.281 mmol) to yield1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{7-[3-(3-hydroxy-pyrrolidin-1-yl)-propoxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-urea(16 mg, 4%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.70 (s, 1H),9.28 (s, 1H), 8.52 (s, 1H), 7.55 (d, 2H), 7.35 (m, 2H), 7.25 (d, 1H),6.95 (d, 1H), 6.45 (s, 1H), 4.70 (brs, 1H), 4.25 (m, 3H), 3.95 (s, 3H),2.80-2.30 (m, 6H), 1.95 (m, 2H), 1.55 (m, 2H), 1.30 (s, 9H); LC-MS (ESI)m/z 577 (M+H)⁺.

Example 32 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-(methylsulfonyl)piperazin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)urea

In the manner described in Example 30(1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-ureafrom Example 27B (225 mg, 0.427 mmol) was reacted with1-methanesulfonyl-piperazine (140.2 mg, 0.854 mmol) to yield1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-(methylsulfonyl)piperazin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)urea (51 mg,18%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.70 (s, 1H), 9.05(s, 1H), 8.55 (s, 1H), 7.58 (d, 2H), 7.35 (m, 2H), 7.22 (d, 1H), 6.95(d, 1H), 6.45 (s, 1H), 4.25 (m, 2H), 3.98 (s, 3H), 3.15 (m, 5H), 2.88(s, 4H), 2.55 (m, 4H), 2.00 (m, 2H), 1.25 (s, 9H); LC-MS (ESI) m/z 654(M+H)⁺.

Example 33 Preparation of(S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea

A stirred solution of(1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-ureafrom Example 27B (102 mg, 0.194 mmol), (S)-3-pyrrolidinol (51 mg, 0.582mmol), N,N-diisopropylethylamine (75 mg, 0.582 mmol) andtetrabutylammonium iodide (71 mg, 0.194 mmol) in dryN,N-dimethylformamide (5 mL) was heated at 60° C. for 20 h. Aftercooling to room temperature, the reaction mixture was partitionedbetween water (50 mL) and ethyl acetate (50 mL) and the organic layerwas separated, washed with brine (50 mL), dried (MgSO₄) and concentratedunder reduced pressure. The residue was purified by preparative HPLC(using a phenyl-hexyl reverse phase column, eluted with gradient ofsolvent B=0.05% HOAC/CH₃CN and solvent A=0.05% HOAc/H₂O). The combinedfractions were washed with saturated aqueous NaHCO₃ and the aqueouslayer extracted with a mixture of 20% methanol in dichloromethane (2×50mL). Concentration under reduced pressure afforded(S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)ureaas a colorless solid (16 mg, 14%). ¹H NMR (300 MHz, CDCl₃) δ 8.59 (brs,1H), 7.68 (brs, 1H), 7.52-7.55 (m, 2H), 7.26-7.35 (m, 4H), 6.95 (m, 1H),6.11 (s, 1H), 4.34-4.40 (m, 3H), 4.04 (s, 3H), 3.00-3.20 (m, 2H), 2.84(m, 1H), 2.67-2.68 (m, 2H), 2.50 (m, 1H), 2.10-2.30 (m, 3H), 1.80 (m,1H), 1.51 (m, 1H), 1.26 (s, 9H); LC-MS (ESI) m/z 577 (M+H)⁺.

Example 34 Preparation of(R)-1-(5-tert-Butylisoxazol-3-yl)-3-(3-(7-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea

(1-(5-Tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea(210 mg, 0.4 mmol) from Example 27B was treated with(R)-(+)-3-pyrrolidinol (65 μL, 0.8 mmol), tetrabutylammonium iodide (148mg, 0.4 mmol) and N,N′-diisopropylethylamine (69 μL, 0.4 mmol) inN,N′-dimethylformamide (4 mL). The mixture was stirred at 50° C. for 5h. After cooling to room temperature water (4 mL) was added and theprecipitating solid filtered off and dried. The solid residue waspurified by preparative HPLC (phenylhexyl reverse phase column). Theobtained solid was triturated with water to give(R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea(37.76 mg, 16%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.60 (s,1H), 9.10 (s, 1H), 8.55 (s, 1H), 7.58-7.56 (m, 2H), 7.40-7.38 (m, 2H),7.25 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 4.70 (s, 1H), 4.31-4.20 (m,3H), 3.99 (s, 3H), 3.32 (s, 1H), 2.81-2.69 (m, 2H), 2.40-2.19 (m, 3H),2.10-1.98 (m, 3H), 1.67-1.4 (m, 1H), 1.27 (s, 9H); LC-MS (ESI) m/z 577(M+H)⁺.

Example 35 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)urea

Example 35A Step 1: To a solution of 4-hydroxy-3-methoxy-benzoic acidmethyl ester (10 g, 54.8 mmol) and potassium carbonate (22.75 g, 164.4mmol) in DMF (100 mL) was added 1-bromo-2-chloro-ethane (22.7 mL, 274mmol). The mixture was heated at 70° C. for 3 h and monitored by TLC.The reaction mixture was diluted with ethyl acetate and washed the ethylacetate layer with water and brine. The organic layer was dried (Na₂SO₄)and concentrated to afford 4-(2-chloro-ethoxy)-3-methoxy-benzoic acidmethyl ester (13.1 gm, 97%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ7.65 (d, 1H), 7.55 (s, 1H), 6.90 (d, 1H), 4.35 (t, 2H), 3.90 (m, 8H).

Example 35A Step 2: The intermediate4-(2-chloro-ethoxy)-3-methoxy-benzoic acid methyl ester (2.7 g, 11.03mmol) was taken in acetic acid (30 mL) and acetic anhydride (6 mL) wasadded. The solution was cooled to 0° C. and 90% nitric acid (2 mL) wasadded. The reaction mixture was stirred for 10-15 minutes at ambienttemperature, then heated to 50° C. for 2 h. Completion of the reactionwas monitored by TLC. The reaction mixture was cooled and was poured onto crushed ice. The precipitate formed was filtered and was dried toafford the pure 4-(2-chloro-ethoxy)-5-methoxy-2-nitro-benzoic acidmethyl ester (2.73 g, 85%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆)δ 7.70 (s, 1H), 7.35 (s, 1H), 4.42 (t, 2H), 4.10-3.90 (m, 5H), 3.80 (m,3H).

Example 35A Step 3: To a solution of4-(2-chloro-ethoxy)-5-methoxy-2-nitro-benzoic acid methyl ester (2.7 g,9.32 mmol) in ethyl acetate (30 mL) was added 10% Pd/C (405 mg) and themixture was stirred under H₂ for 12 h. Completion of the reaction wasmonitored by LCMS. The reaction mixture was filtered using a celite padand was washed with excess ethyl acetate and evaporated to dryness toafford the pure 2-amino-4-(2-chloro-ethoxy)-5-methoxy-benzoic acidmethyl ester (2.40 g, 99%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.15(s, 1H), 6.40 (s, 2H), 6.35 (s, 1H), 4.18 (t, 2H), 3.95 (t, 2H), 3.70 s,3H), 3.65 (s, 3H), LC-MS (ESI) m/z 260 (M+H)⁺.

Example 35A Step 4: To a solution of2-amino-4-(2-chloro-ethoxy)-5-methoxy-benzoic acid methyl ester (2.4 g,9.24 mmol) in ethanol was added formamidine hydrochloride (2.97 g, 36.96mmol). The mixture was heated at 130° C. in sealed tube for 8 h. Theprecipitate formed was filtered and washed with ethanol and dried toafford the pure compound 7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ol(2.25 g, 96%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.95(s, 1H), 7.45 (s, 2H), 7.15 (s, 1H), 4.40 (t, 2H), 4.00 (t, 2H), 3.88(s, 3H), LC-MS (ESI) m/z 255 (M+H)⁺.

Example 35A Step 5: To a solution of4-chloro-7-(2-chloro-ethoxy)-6-methoxy-quinazoline4-chloro-7-(2-chloro-ethoxy)-6-methoxy-quinazoline (3.00 g, 11.77 mmol)in toluene (25 mL) in a pressure vessel was added phosphorousoxychloride (5 mL) and the mixture was heated to 125° C. for 5 h.Completion of the reaction was monitored by LCMS. The mixture wasevaporated to dryness, then excess ethyl acetate was added. The solutionwas washed with water and brine, and dried (Na₂SO₄) then concentrated toafford the pure compound4-chloro-7-(2-chloro-ethoxy)-6-methoxy-quinazoline (2.5 g, 78%) as ayellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.88 (s, 1H), 7.45 (s, 1H),7.35 (s, 1H), 4.50 (t, 2H), 4.05 (t, 2H), 3.95 (s, 3H). LC-MS (ESI) m/z273 (M+H)⁺.

Example 35B: To a solution of(1-(5-tert-butyl-isoxazol-3-yl)-3-(3-hydroxy-phenyl)-urea, 300.13 mg,1.098 mmol) from Example 1A and(4-chloro-7-(2-chloro-ethoxy)-6-methoxy-quinazoline from the previousstep (300 mg, 1.098 mmol) in THF was added Cs₂CO₃ (532.7 mg, 1.64 mmol),and the mixture was heated at 50° C. for 12 h. Completion of thereaction was monitored by LCMS. The reaction mixture was diluted withethyl acetate and the solution was washed with water and brinesuccessively. The organic layer was dried (Na₂SO₄) and concentrated todryness to afford the pure compound1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea(525 mg, 93%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s,1H), 9.00 (s, 1H), 8.55 (s, 1H), 7.57 (s, 2H), 7.40 (m, 2H), 7.22 (d,1H), 6.95 (d, 1H), 6.45 (s, 1H), 4.50 (m, 2H), 4.00 (m, 5H), 1.28 (s,9H); LC-MS (ESI) m/z 512 (M+H)⁺.

Example 35C: To a solution of1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-ureafrom Example 35B (225 mg, 0.439 mmol) in DMF (3 mL) was added morpholine(114.86 mg, 1.318 mmol) followed by diisopropylethylamine (0.229 mL,1.318 mmol) and tetrabutylammonium iodide (162.3 mg, 0.439 mmol). Thereaction mixture was heated at 60° C. for 3 days. Formation of productwas determined by LCMS. The crude reaction mixture was purified bypreparative HPLC (phenomenex phenylhexyl reverse phase column elutedwith gradient of solvent A=0.05% HOAc/H₂O and solvent B=0.05%HOAc/CH₃CN) to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)urea(51 mg, 21%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s, 1H),9.00 (s, 1H), 8.55 (s, 1H), 7.60-7.35 (m, 4H), 7.25 (m, 1H), 6.95 (m,1H), 6.45 (s, 1H), 4.32 (m, 2H), 3.95 (s, 3H), 3.62 (m, 4H), 2.85 (m,2H), 2.65-2.45 (m, 4H), 1.28 (s, 9H); LC-MS (ESI) m/z 563 (M+H)⁺.

Example 36 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-yloxy)phenyl)urea

To a solution of1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-ureafrom Example 35B (225 mg, 0.439 mmol) in DMF (3 mL) was added N-methylpiperazine (0.146 mL, 1.317 mmol) followed by diisopropyl ethylamine(0.229 mL, 1.317 mmol) and tetrabutyl ammonium iodide (162.15 mg, 0.439mmol). The reaction mixture was heated at 60° C. for 2 days. Formationof the product was determined by LCMS. The crude reaction mixture waspurified by preparative HPLC (phenomenex phenylhexyl reverse phasecolumn eluted with gradient of solvent A=0.05% HOAc/H₂O and solventB=0.05% HOAc/CH₃CN) to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-yloxy)phenyl)urea(21 mg, 8%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.80 (s, 1H),9.32 (s, 1H), 8.55 (s, 1H), 7.55 (d, 2H), 7.40 (m, 2H), 7.25 (s, 1H),6.98 (m, 1H), 6.48 (s, 1H), 4.30 (m, 2H), 4.00 (s, 3H), 2.82-2.25 (m,10H), 2.15 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 576 (M+H)⁺.

Example 37 Preparation of1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-urea

1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-ureafrom Example 35B (225 mg, 0.427 mmol) and piperidin-4-yl-methanol (0.103mL, 1.281 mmol) were reacted in the manner described in Example 36 toafford1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-urea(41 mg, 16%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.65 (s, 1H),9.15 (s, 1H), 8.55 (s, 1H), 7.55 (d, 2H), 7.38 (m, 2H), 7.25 (d, 1H),6.95 (d, 1H), 6.45 (s, 1H), 4.45 (brs, 1H), 4.30 (m, 2H), 3.98 (s, 3H),3.25 (m, 2H), 3.00 (m, 2H), 2.75 (m, 2H), 2.00 (m, 2H), 1.65 (d, 2H),1.25 (s, 10H), 1.15 (m, 2H); LC-MS (ESI) m/z 591 (M+H)⁺.

Example 38 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea

1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-ureafrom Example 35B (225 mg, 0.427 mmol) and 2-piperazin-1-yl-ethanol(0.161 mL, 1.317 mmol) were reacted in the manner described in Example36.1-(5-tert-Butylisoxazol-3-yl)-3-(3-(7-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea(33 mg, 13%) was isolated as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ9.70 (brs, 1H), 9.25 (brs, 1H), 8.52 (s, 1H), 7.55 (s, 2H), 7.35 (m,2H), 7.25 (m, 1H), 6.95 (d, 1H), 6.45 (s, 1H), 4.40 (s, 1H), 4.30 (m,2H), 3.95 (s, 3H), 3.45 (m, 2H), 2.85-2.30 (m, 12H), 1.25 (m, 9H); LC-MS(ESI) m/z 606 (M+H)⁺.

Example 39 Preparation of1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{7-[2-(1,1-dioxo-116-thiomorpholin-4-yl)-ethoxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-urea

To a solution of1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-ureafrom Example 35B (225 mg, 0.439 mmol) in DMF (3 mL) was addedthiomorpholine-1,1-dioxide (178 mg, 1.317 mmol) followed bydiisopropylethylamine (0.229 mL, 1.317 mmol) and tetrabutylammoniumiodide (162.15 mg, 0.439 mmol). The reaction mixture was heated at 60°C. for 5 days. Formation of the product was determined by LCMS. Thecrude reaction mixture was purified by preparative HPLC (usingphenyl-hexyl reverse phase column eluted with gradient of solventA=0.05% HOAc/H₂O and solvent B=0.05% HOAc/CH₃CN) to afford1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{7-[2-(1,1-dioxo-116-thiomorpholin-4-yl)-ethoxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-urea(29 mg, 11%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.80-9.15(brs, 2H), 8.52 (s, 1H), 7.55 (d, 2H), 7.35 (m, 2H), 7.25 (d, 1H), 6.92(d, 1H), 6.45 (s, 1H), 4.30 (m, 2H), 3.95 (s, 3H), 3.20-3.00 (m, 8H),2.60 (m, 2H), 1.25 (s, 9H); LC-MS (ESI) m/z 611 (M+H)⁺.

Example 40 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

Example 40A Step 1: To 5-hydroxy-2-nitrobenzaldehyde (1.0 g, 6.0 mmol)in 2.5M NaOH(aq) (10 mL) at 100° C. was added 35% H₂O₂ (12 mL) dropwiseover 10 minutes and the mixture heated at reflux overnight. The solutionwas acidified with 10% H₂SO₄, extracted with EtOAc (2×100 mL), and thecombined organic layers washed with H₂O and brine, dried over MgSO₄,filtered and concentrated in vacuo to give 5-hydroxy-2-nitrobenzoic acid(1.03 g, 5.63 mmol, 94%). LC-MS (ESI) m/z 182 (M−H)⁺.

Example 40A Step 2: To MeOH (125 mL) was added 5-hydroxy-2-nitrobenzoicacid (1.02 g, 5.6 mmol) followed by dropwise addition of thionylchloride (˜4 mL) and the mixture heated at reflux overnight. Thesolution was cooled to room temperature, concentrated in vacuo,reconcentrated twice from MeOH, dissolved in EtOAc, washed with H₂O andbrine, dried over MgSO₄, filtered, and concentrated in vacuo to givemethyl 5-hydroxy-2-nitrobenzoate (1.09 g, 5.5 mmol, 98%). ¹H NMR (300MHz, DMSO-d₆) δ 11.38 (s, 1H), 8.05 (d, 1H), 7.03 (d, 1H), 7.01 (s, 1H),3.82 (s, 3H); LC-MS (ESI) m/z 196 (M−H)⁺.

Example 40A Step 3: To methyl 5-hydroxy-2-nitrobenzoate (1.08 g, 5.5mmol) in DMF (50 mL) was added potassium carbonate (1.52 g, 11 mmol)followed by 1-bromo-2-methoxyethane (1.55 mL, 16.4 mmol) and the mixtureheated at 60° C. overnight. After cooling to room temperature, thereaction was diluted with H₂O, extracted with EtOAc, and the organiclayer washed with H₂O and brine, dried over MgSO₄, filtered,concentrated in vacuo, and purified by column chromatography (12-100%EtOAc/hexanes) to give methyl 5-(2-methoxyethoxy)-2-nitrobenzoate (1.08g, 4.2 mmol, 77%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.13 (d, 1H), 7.31 (s,1H), 7.29 (d, 1H), 4.29 (dd, 2H), 3.86 (s, 3H), 3.68 (dd, 2H), 3.31 (s,3H); LC-MS (ESI) m/z 256 (M+H)⁺.

Example 40A Step 4: To methyl 5-(2-methoxyethoxy)-2-nitrobenzoate (1.08g, 4.2 mmol) under argon was added 10% Palladium on carbon and MeOH (20mL). The flask was flushed with H₂(g) and stirred under H₂ (1 atm) for30 minutes. The mixture was filtered through Celite and concentrated invacuo to give methyl 2-amino-5-(2-methoxyethoxy)benzoate (964 mg, 4.2mmol, 100%). LC-MS (ESI) m/z 226 (M+H)⁺.

Example 40A Step 5: To methyl 2-amino-5-(2-methoxyethoxy)benzoate (964mg, 4.2 mmol) in absolute EtOH (25 mL) was added formamidinehydrochloride (1.4 g, 17.2 mmol) and the mixture heated in a sealed tubeat 130° C. overnight. The mixture was cooled to room temperature andfiltered to give 4-hydroxy-6-(2-methoxyethoxy)quinazoline (871 mg, 4.0mmol, 95%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.42 (br s, 1H), 7.99 (s, 1H),7.61 (d, 1H), 7.50 (d, 1H), 7.43 (dd, 1H), 4.21 (dd, 2H), 3.70 (dd, 2H),3.32 (s, 3H); LC-MS (ESI) m/z 221 (M+H)⁺.

Example 40A Step 6: 4-hydroxy-6-(2-methoxyethoxy)quinazoline (870 mg,3.9 mmol) was reacted with POCl₃ as described in Example 4A Step 2 togive 4-chloro-6-(2-methoxyethoxy)quinazoline (662 mg, 2.8 mmol, 71%).LC-MS (ESI) m/z 239 (M+H)⁺.

Example 40B: The title compound was prepared from1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A(138 mg, 0.5 mmol) and 4-chloro-6-(2-methoxyethoxy)quinazoline fromExample 40A Step 5 (119 mg, 0.5 mmol) using the procedure of Example16C. The crude product was purified by column chromatography (25-100%EtOAc/hexanes) to give1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea(45 mg, 0.094 mmol, 20%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.59 (s, 1H), 9.01(s, 1H), 8.62 (s, 1H), 7.94 (d, 1H), 7.74-7.64 (m, 3H), 7.60 (s, 1H),7.42 (t, 1H), 7.27 (d, 1H), 6.99 (d, 1H), 6.48 (s, 1H), 4.37-4.31 (m,2H), 3.78-3.71 (m, 2H), 3.34 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 478(M+H)⁺.

Example 41 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazolin-4-ylthio)phenyl)urea

Example 41A Step 1: To DMF (80 mL) was added potassium carbonate (5.7 g,41.1 mmol) and methyl 3-hydroxy-4-methoxybenzoate (5.0 g, 27.4 mmol).The mixture was cooled to 0° C. and 1-bromo-3-chloropropane (8.64 g,57.9 mmol) in DMF (10 mL) was added dropwise over 30 minutes. Themixture was allowed to warm to room temperature overnight. Afterremoving most of the DMF in vacuo, the remaining oil was diluted withH₂O and filtered to give methyl 3-(3-chloropropoxy)-4-methoxybenzoate(6.65 g, 25.8 mmol, 94%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.61 (d, 1H), 7.47(s, 1H), 7.09 (d, 1H), 4.12 (t, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.78(t, 2H), 2.23-2.15 (m, 2H); LC-MS (ESI) m/z 259 (M+H)⁺.

Example 41A Step 2: In the manner described in Example 16A Step 2 methyl3-(3-chloropropoxy)-4-methoxybenzoate (6.65 g, 25.7 mmol) was reactedwith nitric acid to give methyl5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate (6.70 g, 22.1 mmol, 86%).¹H NMR (300 MHz, DMSO-d₆) δ 7.65 (s, 1H), 7.37 (s, 1H), 4.26 (t, 2H),3.89 (s, 3H), 3.81 (s, 3H), 3.76 (t, 2H), 2.26-2.18 (m, 2H).

Example 41A Step 3: In the manner described in Example 16A Step 3,methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate (6.70 g, 22.1 mmol)in EtOAc (100 mL) was reacted with 10% palladium on carbon as describedin Example 16A Step 3 to give methyl2-amino-5-(3-chloropropoxy)-4-methoxybenzoate (6.0 g, 22.0 mmol, 99%).¹H NMR (300 MHz, DMSO-d₆) δ 7.18 (s, 1H), 6.49 (br s, 2H), 6.37 (s, 1H),3.93 (t, 2H), 3.82-3.71 (m, 8H), 2.14-2.06 (m, 2H); LC-MS (ESI) m/z 274(M+H)⁺.

Example 41A Step 4: In the manner described in Example 16A Step 4,methyl 2-amino-5-(3-chloropropoxy)-4-methoxybenzoate (6.0 g, 21.9 mmol)in EtOAc from the previous step was reacted with formamidinehydrochloride as in Example 16A Step 4 to give6-(3-chloropropoxy)-4-hydroxy-7-methoxyquinazoline (4.48 g, 16.7 mmol,76%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (br s, 1H), 8.00 (s, 1H), 7.47(s, 1H), 7.15 (s, 1H), 4.19 (t, 2H), 3.97 (s, 3H), 3.81 (t, 2H),2.27-2.19 (m, 2H); LC-MS (ESI) m/z 269 (M+H)⁺.

Example 41B Step 1: To N,N-dimethylformamide (40 mL, purged with argon)was added cesium carbonate (1.43 g, 4.4 mmol) and6-(3-chloropropoxy)-4-hydroxy-7-methoxyquinazoline from the previousstep (1.08 g, 4.0 mmol), at which point methanethiol (g) was bubbledinto the reaction for 10 minutes. The mixture was stirred at roomtemperature for an additional 60 minutes, poured into H₂O and filteredto give 4-hydroxy-7-methoxy-6-(3-(methylthio)propoxy)quinazoline (877mg, 3.13 mmol, 78%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.07 (br s, 1H), 7.99(s, 1H), 7.45 (s, 1H), 7.13 (s, 1H), 4.14 (t, 2H), 3.91 (s, 3H), 2.64(t, 2H), 2.05 (s, 3H), 2.04-1.97 (m, 2H); LC-MS (ESI) m/z 281 (M+H)⁺.

Example 41B Step 2: To dichloromethane (20 mL) at 0° C. was added4-hydroxy-7-methoxy-6-(3-(methylthio)propoxy)quinazoline (870 mg, 3.1mmol) followed by 3-chloroperbenzoic acid (2.7 g, 15.7 mmol). Thesolution was stirred for 10 minutes, diluted with DCM, and filtered togive 4-hydroxy-7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazoline (710mg, 2.28 mmol, 73%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.07 (br s, 1H), 8.00(s, 1H), 7.45 (s, 1H), 7.15 (s, 1H), 4.19 (t, 2H), 3.91 (s, 3H), 3.30(t, 2H), 3.05 (s, 3H), 2.26-2.15 (m, 2H); LC-MS (ESI) m/z 313 (M+H)⁺.

Example 41B Step 3: The intermediate4-hydroxy-7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazoline (700 mg,2.24 mmol) from the previous step was reacted with POCl₃ in the mannerdescribed in Example 4A Step 2 to give4-chloro-7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazoline (480 mg,1.45 mmol, 65%). LC-MS (ESI) m/z 331 (M+H)⁺.

Example 41C: 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (124mg, 0.45 mmol) from Example 1A was treated with cesium carbonate (294mg, 0.90 mmol) in anhydrous tetrahydrofuran (2.5 mL). The mixture wasstirred at room temperature for 30 minutes.4-chloro-7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazoline from theprevious step (149 mg, 0.45 mmol) was then added to the suspension andthe mixture heated to 60° C. for 2 h. After cooling to room temperaturethe crude mixture was taken in ethyl acetate/water and extracted. Theorganic fractions were combined, dried (MgSO₄) and concentrated underreduced pressure. The residue was purified by preparative HPLC(phenylhexyl reverse phase column) to give1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazolin-4-ylthio)phenyl)urea(10.3 mg, 4%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.64 (s, 1H), 9.08 (s, 1H),8.57 (s, 1H), 7.58 (s, 2H), 7.43-7.38 (m, 2H), 7.27 (d, 1H), 6.97 (d,1H), 6.48 (s, 1H), 4.34-4.32 (m, 2H), 4.02 (s, 3H), 3.33-3.30 (m, 2H),3.06 (s, 3H), 3.29-3.27 (m, 2H), 1.30 (s, 9H); LC-MS (ESI) m/z 570(M+H)⁺.

Example 42 Preparation of1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazolin-4-yloxy)phenyl)urea

Example 42A Step 1: Prepared from ethyl 2-isobutyrate (10 g, 74.62 mmol)according to the method described for 4-methyl-3-oxopentanenitrile inExample 122A Step 1, to afford 4-fluoro-4-methyl-3-oxopentanenitrile asa yellow oil (8 g, 83%) which was used in the next step without furtherpurification. ¹H NMR (300 MHz, CDCl₃) δ 3.82 (s, 2H), 1.54 (d, J=21 Hz,6H).

Example 42A Step 2: Prepared from 4-fluoro-4-methyl-3-oxopentanenitrile(6 g, 47 mmol) according to the method described for3-isopropylisoxazol-5-amine in Example 122A Step 2, to afford3-(2-fluoropropan-2-yl)isoxazol-5-amine as a light yellow solid (4.83 g,71%) which was used in the next step without further purification. ¹HNMR (300 MHz, CDCl₃) δ 5.19 (s, 1H), 4.48 (brs, 2H), 1.68 (d, J=21 Hz,6H); LC-MS (ESI) m/z 145 (M+H)⁺.

Example 42A Step 3: Prepared from3-(2-fluoropropan-2-yl)isoxazol-5-amine (4.83 g, 33.54 mmol) accordingto the method described for phenyl 3-isopropylisoxazol-5-ylcarbamate inExample 122A Step 3, to afford phenyl3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate as a colorless solid (6.04g, 68%). ¹H NMR (300 MHz, CDCl₃) δ 7.80 (brs, 1H), 7.39-7.45 (m, 2H),7.18-7.32 (m, 3H), 6.27 (s, 1H), 1.74 (d, J=21 Hz, 6H); LC-MS (ESI) m/z265 (M+H)⁺.

Example 42B: To THF (10 mL) was added phenyl3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from the previous step(500 mg, 1.9 mmol), 3-aminophenol (207 mg, 1.9 mmol) anddimethylaminopyridine (60 mg, 0.5 mmol) and the mixture stirredovernight at room temperature. The mixture was concentrated in vacuo andpurified by chromatography on silica gel (10-50% EtOAc/hexanes) toafford 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-hydroxyphenyl)urea(390 mg, 1.4 mmol, 74%). LC-MS (ESI) m/z 280 (M+H)⁺.

Example 42C: The title compound was prepared from1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-hydroxyphenyl)urea (84 mg,0.3 mmol) and4-chloro-7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazoline from Example41B Step 1 (76 mg, 0.23 mmol) using the procedure described in Example16C. The crude product was purified by chromatography on silica gel(25-100% EtOAc/hexanes) to afford1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazolin-4-yloxy)phenyl)urea(81 mg, 0.14 mmol, 61%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.42 (br s, 1H),9.11 (s, 1H), 8.57 (s, 1H), 7.63-7.58 (m, 2H), 7.47-7.40 (m, 2H), 7.32(d, 1H), 7.00 (d, 1H), 6.15 (s, 1H), 4.32 (t, 2H), 4.02 (s, 3H),3.41-3.29 (m, 2H), 3.06 (s, 3H), 2.31-2.22 (m, 2H), 1.66 (d, 6H); LC-MS(ESI) m/z 574 (M+H)⁺.

Example 43 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

Example 43A: 7-(Benzyloxy)quinazolin-4(3H)-one (5 g, 19.8 mmol) wastreated with thionyl chloride (50 mL) and anhydrousN,N′-dimethylformamide (0.5 mL) and heated to 80° C. for 1.5 h. Thesolvent was removed under reduced pressure and the residue dissolved indichloromethane, cooled to 0° C. and the pH adjusted to basic (pH=8)with a saturated solution of sodium bicarbonate. The organic layer wasseparated, the water extracted with ethyl acetate and the organicscombined, dried (MgSO₄) and concentrated under reduced pressure to give7-(benzyloxy)-4-chloroquinazoline (4.75 g, 89%), which was used directlyin the next step without further purification. ¹H NMR (300 MHz, DMSO-d₆)δ 9.13 (s, 1H), 8.18 (d, 1H), 7.97-7.46 (m, 4H), 7.46-7.35 (m, 4H), 5.35(s, 2H); LC-MS (ESI) m/z 271 (M+H)⁺.

Example 43B Step 1: Following to the procedure described in Example 41C,1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (1.02 g, 3.7 mmol)from Example 1A was reacted with 7-(benzyloxy)-4-chloroquinazoline (1 g,3.7 mmol) and cesium carbonate (24 g, 7.4 mmol) in anhydroustetrahydrofuran (10 mL) and the mixture was heated at 50° C. overnight.The crude product was triturated with dichloromethane to give1-(3-(7-(benzyloxy)quinazolin-4-yloxy)phenyl)-3-(5-tert-butylisoxazol-3-yl)urea(725 mg, 38%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.59 (s, 1H), 9.01(s, 1H), 8.65 (s, 1H), 8.29 (d, 1H), 7.57-7.38 (m, 9H), 7.28 (d, 1H),6.98 (d, 1H), 6.48 (s, 1H), 5.37 (s, 2H), 1.27 (s, 9H); LC-MS (ESI) m/z510 (M+H)⁺.

Example 43B Step 2:1-(3-(7-(Benzyloxy)quinazolin-4-yloxy)phenyl)-3-(5-tert-butylisoxazol-3-yl)urea(725 mg, 1.42 mmol) was treated with trifluoroacetic acid (7 mL) andheated at 85° C. for 3 h. The solvent was removed under reduced pressureand the residue dissolved in ethyl acetate/water. The solution wasneutralized with saturated sodium bicarbonate (pH=8) and the organiclayer separated. After extraction of the aqueous phase with ethylacetate, the organic fractions were combined, dried (MgSO₄) andconcentrated under reduced pressure. The solid was triturated with ethylacetate to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-hydroxyquinazolin-4-yloxy)phenyl)urea(358 mg, 60%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.92 (s, 1H),9.64 (s, 1H), 9.07 (s, 1H), 8.58 (s, 1H), 8.24 (d, 1H), 7.57 (s, 1H),7.41 (t, 1H), 7.30 (d, 2H), 7.20 (s, 1H), 6.97 (d, 1H) 6.49 (s, 1H),1.27 (s, 9H); LC-MS (ESI) m/z 420 (M+H)⁺.

Example 43B Step 3:1-(5-tert-Butylisoxazol-3-yl)-3-(3-(7-hydroxyquinazolin-4-yloxy)phenyl)urea(126 mg, 0.3 mmol) was treated with cesium carbonate (117 mg, 0.36 mmol)in anhydrous N,N′-dimethylformamide (3 mL) and stirred at roomtemperature for 30 minutes. 2-Bromoethylmethyl ether (50 mg, 0.36 mmol)was added and the mixture was stirred at 50° C. overnight. Cesiumcarbonate was filtered off and the residue purified by preparative HPLC(phenylhexyl reverse phase column) to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea(21.16 mg, 15%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (bs, 1H),9.00 (bs, 1H), 8.65 (s, 1H), 8.27 (d, 1H), 7.57 (s, 1H), 7.41-7.38 (m,3H), 7.28 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 4.34 (bs, 2H), 3.76 (bs,2H), 3.35 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 478 (M+H)⁺.

Example 44 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazolin-4-ylthio)phenyl)urea

Example 44A Step 1: To DMSO (2.75 mL, 38.3 mmol) was added3-aminothiophenol (4.07 mL, 38.3 mmol) and the mixture was heated at 90°C. for 4 hours and then poured into 6N HCl (40 mL). The yellow solid wasfiltered and dried under vacuum to give 3,3′-disulfanediyldianiline-xHCl(6.7 g, 17-23 mmol). LC-MS (ESI) m/z 249 (M+H)⁺.

Example 44A Step 2: To DMF (50 mL) was added triethylamine (10 mL),3,3′-disulfanediyldianiline-xHCl (1.98 g) and5-tert-butyl-3-isocyanatoisoxazole (1.81 g, 11 mmol), and the mixtureheated at 50° C. overnight. After cooling to room temperature, thereaction was poured into H₂O, extracted with EtOAc (2×250 mL), and thecombined org layers were washed with brine, dried over MgSO₄, filtered,concentrated in vacuo, and purified by column chromatography (25-100%EtOAc/hexanes) to give1,1′-(3,3′-disulfanediylbis(3,1-phenylene))bis(3-(5-tert-butylisoxazol-3-yl)urea)(2.2 g, 3.8 mmol). LC-MS (ESI) m/z 581 (M+H)⁺.

Example 44A Step 3: To glacial acetic acid (40 mL) was added1,1′-(3,3′-disulfanediylbis(3,1-phenylene))bis(3-(5-tert-butylisoxazol-3-yl)urea)(2.2 g, 3.8 mmol) and Zinc dust (1.24 g, 19 mmol). The mixture washeated at 50° C. overnight, cooled to r.t, and the AcOH decanted andconcentrated. The crude solid was sonicated in 1N aqueous NaHSO₄,extracted with EtOAc, the organic layer dried over MgSO₄, filtered,concentrated in vacuo, and purified by column chromatography (15-50%EtOAc/hexanes) to give1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea (1.08 g, 3.7mmol, 49%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.51 (s, 1H), 8.79 (s, 1H), 7.50(s, 1H), 7.20-7.09 (m, 2H), 6.91 (d, 1H), 6.50 (s, 1H), 5.50 (br s, 1H),1.28 (s, 9H); LC-MS (ESI) m/z 291 (M+H)⁺.

Example 44B: To a suspension of sodium hydride (11 mg, 0.44 mmol) inanhydrous tetrahydrofuran (2 mL) cooled to 0° C., was added1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea from the previousstep (117 mg, 0.40 mmol) as a solution in tetrahydrofuran (1 mL) and themixture stirred at 0° C. for 30 minutes. To this suspension4-chloro-7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazoline from Example41B Step 1 (133 mg, 0.40 mmol) was added and the resulting mixture wasstirred at 0° C. and slowly allowed to reach room temperature. Afterstirring for additional 1 h, the mixture was taken up in ethylacetate/water and extracted. The combined organic layers were dried(MgSO₄) and concentrated under reduced pressure. The residue waspurified by preparative HPLC (Phenomenex phenylhexyl reverse phasecolumn) to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazolin-4-ylthio)phenyl)urea(10.30 mg, 4%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.73 (bs, 1H),9.19 (bs, 1H), 8.70 (s, 1H), 7.85 (s, 1H), 7.53-7.27 (m, 5H), 6.49 (s,1H), 4.32 (bs, 2H), 4.01 (s, 3H), 3.35 (2H), 3.07 (s, 3H), 2.28 (bs,2H), 1.28 (s, 9H); LC-MS (ESI) m/z 586 (M+H)⁺.

Example 45 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea

1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described inExample 44A (223 mg, 0.83 mmol) was treated with cesium carbonate (325mg, 1.0 mmol) in anhydrous tetrahydrofuran (8 mL). The mixture wasstirred at room temperature for 30 minutes.4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline (149 mg, 0.45 mmol)from Example 15A was added to the suspension and the mixture heated to50° C. overnight. After cooling to room temperature the mixture wasconcentrated under reduced pressure and the residue purified by silicagel chromatography (ethyl acetate/dichloromethane 1:1) to give1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea(218 mg, 50%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s, 1H), 9.00(s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.52-7.27 (m, 5H), 6.49 (s, 1H),4.32 (bs, 2H), 4.00 (s, 3H), 3.77 (bs, 2H), 3.36 (s, 3H), 1.27 (s, 9H);LC-MS (ESI) m/z 524 (M+H)⁺.

Example 46 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

To a slurry of sodium hydride (53 mg, 2.2 mmol) in THF (20 mL) was addedthe thiol described in Example 44A (582 mg, 2.0 mmol), prepared asdescribed previously, and the solution stirred at r.t until gasevolution ceased. After an additional 30 minutes of stirring,4-chloro-6,7-dimethoxyquinazoline (448 mg, 2.0 mmol) was added. Afterstirring at r.t for 4 hours, the reaction was concentrated in vacuo. Theresulting solid was diluted with EtOAc, the organic layer washed withaqueous sat. NaHCO₃ and brine, dried over MgSO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography (25-100% EtOAc/hexanes) to give1-(5-tert-butylisoxazol-3-yl)-3-(3-(2-chloro-6,7-dimethoxyquinazolin-4-ylthio)phenyl)ureaas a white solid. The compound was dissolved in EtOAc (5 mL) and 4N HClin dioxane (0.2 mL, 0.8 mmol) was added. The mixture was sonicated,stirred and concentrated in vacuo to give the product (300 mg, 0.58mmol, 29%) as the mono-hydrochloride. ¹H NMR (300 MHz, DMSO-d₆) δ 9.74(s, 1H), 9.50 (s, 1H), 8.79 (s, 1H), 7.86 (s, 1H), 7.55 (d, 1H), 7.45(t, 1H), 7.38 (s, 2H), 7.30 (d, 1H), 6.50 (s, 1H), 4.00 (s, 6H), 1.28(s, 9H); LC-MS (ESI) m/z 480 (M+H)⁺.

Example 47 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-difluoroquinazolin-4-ylthio)phenyl)urea

The title compound was prepared from1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described inExample 44A (87 mg, 0.3 mmol) and 4-chloro-6,7-difluoroquinazoline (60mg, 0.3 mmol) from Example 4A Step 2 as described in Example 46 to give145-tert-butylisoxazol-3-yl)-3-(3-(6,7-difluoroquinazolin-4-ylthio)phenyl)urea (50 mg, 0.11 mmol, 37%). ¹H NMR (300MHz, DMSO-d₆) δ 9.61 (s, 1H), 9.05 (s, 1H), 8.88 (s, 1H), 8.34 (dd, 1H),8.09 (dd, 1H), 7.88 (s, 1H), 7.53 (d, 1H), 7.47 (t, 1H), 7.30 (d, 1H),6.49 (s, 1H), 1.28 (s, 9H); LC-MS (ESI) m/z 478 (M+Na)⁺.

Example 48 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared from1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described inExample 44A (116 mg, 0.4 mmol) and 4-chloro-7-methoxyquinazoline (78 mg,0.4 mmol) as described in Example 46 and its corresponding hydrochloridesalt was prepared as described in Example X4 Step 2 to give1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxyquinazolin-4-ylthio)phenyl)ureaas the mono-hydrochloride (143 mg, 0.30 mmol, 75%). ¹H NMR (300 MHz,DMSO-d₆) δ 9.77 (s, 1H), 9.55 (s, 1H), 8.85 (s, 1H), 8.20 (d, 1H), 7.87(s, 1H), 7.55 (d, 1H), 7.48-7.42 (m, 2H), 7.38 (s, 1H), 7.29 (d, 1H),6.50 (s, 1H), 3.99 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 450 (M+H)⁺.

Example 49 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared from1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described inExample 44A (87 mg, 0.3 mmol) and 4-chloro-6-methoxyquinazoline (59 mg,0.3 mmol) as described in Example 46 and its corresponding hydrochloridesalt was prepared as described in Example 4B Step 2 to give1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxyquinazolin-4-ylthio)phenyl)ureaas the mono-hydrochloride (76 mg, 0.15 mmol, 50%). ¹H NMR (300 MHz,DMSO-d₆) δ 9.75 (s, 1H), 9.49 (s, 1H), 8.80 (s, 1H), 7.95 (d, 1H), 7.87(s, 1H), 7.71 (dd, 1H), 7.55 (d, 1H), 7.49-7.42 (m, 2H), 7.29 (d, 1H),6.50 (s, 1H), 4.00 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 450 (M+H)⁺.

Example 50 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-ethoxy-6-methoxyquinazolin-4-ylthio)phenyl]urea

A mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)ureadescribed in Example 44A (0.146 g 0.5 mmol),4-chloro-7-ethoxy-6-methoxyquinazoline from Example 6B Step 1 (0.12 g,0.5 mmol), and Cs₂CO₃ (0.161 mg, 0.5 mmol) in isopropanol (10 mL) washeated at 70° C. for 7 hours. It was quenched with water and extractedwith CH₂Cl₂. Extracts were dried over MgSO₄ and concentrated underreduced pressure. It was purified by silica gel chromatography withEtOAc/hexane as eluant to afford1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-ethoxy-6-methoxyquinazolin-4-ylthio)phenyl]ureaas solid (0.118 g, 48%). ¹H NMR (300 MHz, CDCl₃) δ 9.3 (br, 1H), 8.74(s, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.62 (d, 1H), 7.37 (m, 3H), 7.25(1H), 5.91 (s, 1H), 4.29 (q, 2H), 4.06 (s, 3H), 1.58 (t, 3H), 1.32 (s,9H); LC-MS (ESI) m/z 494 (M+H)⁺.

Example 51 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-[3-(6,7-diethoxyquinazolin-4-ylthio)phenyl]urea

As described in Example 50 the intermediate1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described inExample 44A (0.117 g, 0.4 mmol) was reacted with4-chloro-6,7-diethoxyquinazoline (0.101 g, 0.4 mmol) from Example 13A,and Cs₂CO₃ (0.130 g, 0.4 mmol) in isopropanol (10 mL) at 70° C. for 4hours, to afford1-(5-tert-butylisoxazol-3-yl)-3-[3-(6,7-diethoxyquinazolin-4-ylthio)phenyl]ureaas solid (0.131 g, 65%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.59 (s, 1H), 9.03(s, 1H), 8.68 (s, 1H), 7.84 (s, 1H), 7.50 (d, 1H), 7.44 (t, 1H), 7.33(m, 2H), 7.29 (d, 1H), 6.49 (s, 1H), 4.26 (m 4H), 1.45 (m, 6H), 1.28 (s,9H); LC-MS (ESI) m/z 508 (M+H)⁺.

Example 52 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}ureahydrochloride

Example 52A: As described in Example 50 the intermediate1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described inExample 44A (0.105 g, 0.36 mmol) was reacted with4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline from Example 7A (0.134g, 0.5 mmol), and Cs₂CO₃ (0.325 g, 1 mmol) in isopropanol (8 mL) at 70°C. for 4 hours, to afford1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}ureaas solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s, 1H), 9.00 (s, 1H), 8.69(s, 1H), 7.84 (m, 1H), 7.51 (m, 1H), 7.44 (t, 1H), 7.37 (s, 1H), 7.34(s, 1H), 7.28 (m 1H), 6.49 (s, 1H), 4.33 (t, 2H), 4.00 (s, 3H), 3.76 (t,2H), 3.34 (s, 3H), 1.28 (s, 9H).

Example 52B: To1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}ureawas added 1.0 M HCl in Et₂O solution (2 eq.) in the manner described inExample 6B Step 2 to afford1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}ureahydrochloride as solid (0.16 g, 80%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.65(s, 1H), 9.23 (s, 1H), 8.72 (s, 1H), 7.85 (s, 1H), 7.52 (d, 1H), 7.44(t, 1H), 7.38 (s, 1H), 7.36 (s, 1H), 7.28 (d, 1H), 6.49 (s, 1H), 4.34(t, 2H), 4.01 (s, 3H), 3.76 (t, 2H), 3.34 (s, 3H), 1.28 (s, 9H); LC-MS(ESI) m/z 524 (M+H)⁺.

Example 53 Preparation of1-{3-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-(5-tert-butylisoxazol-3-yl)ureahydrochloride

Example 53A: As described in Example 50, a mixture of the intermediate1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described inExample 44A (0.117 g, 0.4 mmol),4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (0.125 g, 0.4 mmol) fromExample 12A, and Cs₂CO₃ (0.20 g, 0.6 mmol) in isopropanol (5 mL) washeated at 90° C. overnight, to afford1-{3-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-(5-tert-butylisoxazol-3-yl)urea.as solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s, 1H), 8.99 (s, 1H), 8.68(s, 1H), 7.84 (m, 1H), 7.51 (m, 1H), 7.46 (t, 1H), 7.39 (s, 1H), 7.38(s, 1H), 7.28 (dd 1H), 6.49 (s, 1H), 4.34 (m 4H), 3.78 (m, 4H), 3.37 (s,3H), 3.35 (s, 3H), 1.28 (s, 9H).

Example 53B: As described in Example 6B Step 2, to a solution of1-{3-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-(5-tert-butylisoxazol-3-yl)ureain CH₂Cl₂ and MeOH was added 1.0 M HCl/Et₂O solution (2 eq.), to afford1-{3-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-(5-tert-butylisoxazol-3-yl)ureahydrochloride as solid (0.098 g, 40%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.66(s, 1H), 9.23 (s, 1H), 8.72 (s, 1H), 7.85 (s, 1H), 7.52 (d, 1H), 7.44(t, 1H), 7.44 (s, 1H), 7.38 (s, 1H), 7.28 (d, 1H), 6.49 (s, 1H), 4.35(m, 4H), 3.78 (m, 4H), 3.37 (s, 3H), 3.35 (s, 3H), 1.28 (s, 9H); LC-MS(ESI) m/z 568 (M+H)⁺.

Example 54 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-[3-(7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-ylthio)phenyl]ureahydrochloride

Example 54A: According to the procedure described in Example 50, amixture of the intermediate145-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described inExample 44A (0.105 g, 0.36 mmol),4-chloro-7,8-dihydro-[1,4]dioxino[2,3-g]quinazoline described in Example14A (0.111 g, 0.5 mmol), and Cs₂CO₃ (0.326 g, 1 mmol) in isopropanol (7mL) was heated at 60° C. for 2 hours, to afford1-(5-tert-butylisoxazol-3-yl)-3-[3-(7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-ylthio]phenyl)ureaas solid.

Example 54B: According to the procedure described in Example 6B Step 2,to a solution of1-(5-tert-butylisoxazol-3-yl)-3-[3-(7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-ylthio)phenyl]ureain CH₂Cl₂ and MeOH was added 1.0 M HCl/Et₂O solution, to afford1-(5-tert-butylisoxazol-3-yl)-3-[3-(7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-ylthio)phenyl]ureahydrochloride as solid (0.113 g, 61%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.66(s, 1H), 9.23 (s, 1H), 8.69 (s, 1H), 7.83 (m, 1H), 7.56 (s, 1H), 7.51(d, 1H), 7.44 (t, 1H), 7.38 (s, 1H), 7.27 (d, 1H), 6.49 (s, 1H), 4.47(m, 4H), 1.28 (s, 9H); LC-MS (ESI) m/z 478 (M+H)⁺.

Example 55 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-{3-[7-methoxy-5-(tetrahydro-2H-pyran-4-ylthio)quinazolin-4-yloxy]phenyl}urea

According to the procedure described in Example 50, a mixture of theintermediate 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)ureadescribed in Example 44A (0.204 g, 0.7 mmol),4-chloro-7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazoline fromExample 94A (0.212 g, 0.72 mmol), and Cs₂CO₃ (0.326 g, 1 mmol) inisopropanol (10 mL) was heated at 60° C. for 4 hours, to afford1-(5-tert-butylisoxazol-3-yl)-3-{3-[7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-ylthio]phenyl}ureaas solid (0.086 g, 22%). ¹H NMR (300 MHz, CDCl₃) δ 9.3 (s, 1H), 8.60 (s,1H), 7.82 (s, 1H), 7.76 (s, 1H), 7.65 (d, 1H), 7.41 (t, 1H), 7.33 (d,1H), 6.86 (d, 1H), 6.54 (d, 1H), 5.90 (s, 1H), 4.78 (m 1H), 4.18 (m,2H), 3.94 (s, 3H), 3.69 (m, 2H), 2.19 (m, 2H), 2.11 (m, 2H), 1.33 (s,9H); LC-MS (ESI) m/z 550 (M+H)⁺.

Example 56 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-ethoxy-7-methoxyquinazolin-4-ylthio)phenyl)urea

In a sealed reaction vessel1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described inExample 44A (333 mg, 1.14 mmol) was dissolved in 11 mL of THF. To thissolution was added cesium carbonate (447 mg, 1.37 mmol), and thesolution stirred for 30 minutes. At the end of this time4-chloro-6-ethoxy-7-methoxyquinazoline (273 mg, 1.14 mmol) from Example10A and the reaction heated to 50° C. for 48 hours. The reaction wasconcentrated and purified by silica gel chromatography eluting with anethyl acetate/dichloromethane gradient 0-50% over 75 minutes.Concentration of the main peak gave the title compound (374 mg, 66.5%yield). ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s, 1H), 9.01 (s, 1H), 8.69 (s,1H), 7.48 (s, 1H), 7.55-7.25 (m, 5H), 6.49 (s, 1H), 4.25 (m, 2H), 3.99(s, 3H), 1.47 (m, 3H), 1.32 (s, 9H). LCMS (ESI) m/z 494 (M+H)

Example 57 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(piperidin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea

Example 57A: The intermediate1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described inExample 44A (1.01 g, 3.5 mmol) was reacted with4-chloro-6-(3-chloropropoxy)-7-methoxyquinazoline (1.0 g, 3.5 mmol) fromExample 21A Step 5 as described in Example 46 to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea(1.69 g, 3.12 mmol, 89%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.59 (s, 1H), 9.01(s, 1H), 8.70 (s, 1H), 7.85 (s, 1H), 7.51 (d, 1H), 7.44 (t, 1H), 7.36(s, 2H), 7.28 (d, 1H), 6.49 (s, 1H), 4.31 (t, 2H), 4.00 (s, 3H), 3.85(t, 2H), 2.37-2.25 (m, 2H), 1.29 (s, 9H); LC-MS (ESI) m/z 542 (M+H)⁺.

Example 57B: The urea from the previous step (200 mg, 0.37 mmol) wastreated with piperidine (109 μL, 1.11 mmol), tetrabutylammonium iodide(136 mg, 0.37 mmol) and N,N′-diisopropylethylamine (129 μL, 0.74 mmol)in N,N′-dimethylformamide (3 mL). The mixture was heated to 60° C. for56 h and cooled to room temperature. Water (10 mL) was added and thesolid filtered off and dried. The crude solid was purified bypreparative HPLC (phenylhexyl reverse phase column) and the obtainedsolid triturated with water (10 mL) and drops of methanol, then filteredoff and dried under high vacuum to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(piperidin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea(24.05 mg, 11%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.59 (s, 1H),9.01 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.52-7.41 (m, 2H), 7.35-7.26(m, 3H), 6.49 (s, 1H), 4.22-4.18 (m, 2H), 3.99 (s, 3H), 2.51-2.36 (m,6H), 1.99-1.95 (m, 2H), 1.51-1.49 (m, 4H), 1.39-1.38 (m, 2H), 1.27 (s,9H); LC-MS (ESI) m/z 591 (M+H)⁺.

Example 58 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared as described in Example 57B by using1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)ureafrom Example 57B (200 mg, 0.37 mmol) and 4-piperidinemethanol (127 mg,1.11 mmol) to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea(35.75 mg, 58%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.60 (s, 1H),9.02 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.53-7.43 (m, 2H), 7.34-7.26(m, 3H), 6.49 (s, 1H), 4.42-4.40 (m, 1H), 4.22-4.18 (m, 2H), 4.18 (s,3H), 3.25-3.21 (m, 2H), 2.91 (d, 2H), 2.50-2.47 (m, 2H), 2.00-1.88 (m,4H), 1.64 (d, 2H), 1.27 (s, 9H), 1.16-1.12 (m, 2H); LC-MS (ESI) m/z 621(M+H)⁺.

Example 59 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea

The title compound was prepared as described in Example 57B by using1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)ureafrom Example 57B (200 mg, 0.37 mmol) and N-methyl piperazine (123 μL,1.11 mmol) to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea(15.75 mg, 7%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.59 (s, 1H),9.01 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.52-7.43 (m, 2H), 7.34-7.26(m, 3H), 6.49 (s, 1H), 4.20 (bs, 2H), 3.99 (s, 3H), 2.46-2.34 (m, 10H),2.14 (s, 3H), 1.99-1.97 (m, 2H), 1.27 (s, 9H); LC-MS (ESI) m/z 606(M+H)⁺.

Example 60 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(4-(methylsulfonyl)piperazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea

The title compound was prepared as described in Example 57B by using1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)ureafrom Example 57B (200 mg, 0.37 mmol) and N-methylsulfonyl-piperazine(182 mg, 1.11 mmol) to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(4-(methylsulfonyl)piperazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea(54.17 mg, 22%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.59 (s, 1H),9.00 (s, 1H), 9.69 (s, 1H), 7.85 (s, 1H), 7.51-7.26 (m, 5H), 6.49 (s,1H), 4.22 (bs, 2H), 3.99 (s, 3H), 3.14 (s, 4H), 2.86 (s, 3H), 2.20-1.90(m, 2H), 1.28 (s, 9H); LC-MS (ESI) m/z 670 (M+H)⁺.

Example 61 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared as described in Example 57B by using1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)ureafrom Example 57B (200 mg, 0.37 mmol) and 1-(2-hydroxyethyl)piperazine(136 μL, 1.11 mmol) to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea(17.86 mg, 7%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.62 (bs, 1H),9.05 (bs, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.65-7.36 (m, 5H), 6.49 (s,1H), 4.21 (bs, 2H), 3.99 (s, 3H), 3.70-3.19 (m, 6H), 2.50-2.29 (m, 8H),1.98 (bs, 2H), 1.27 (s, 9H); LC-MS (ESI) m/z 636 (M+H)⁺.

Example 62145-tert-butyl-isoxazol-3-yl)-3-(3-{6-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-7-methoxy-quinazolin-4-ylsulfanyl}-phenyl)-urea

The title compound was prepared as described in Example 57B by using1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)ureafrom Example 57B (200 mg, 0.37 mmol) and thiomorpholine 1,1-dioxide (150mg, 1.11 mmol) to afford1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-7-methoxy-quinazolin-4-ylsulfanyl}-phenyl)-urea(54.51 mg, 23%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.59 (s, 1H),9.01 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.52-7.27 (m, 5H), 6.49 (s,1H), 4.25-4.21 (m, 2H), 3.99 (s, 3H), 3.11 (bs, 4H), 2.95 (bs, 4H),2.70-2.65 (m, 2H), 2.01-1.97 (m, 2H), 1.27 (s, 9H); LC-MS (ESI) m/z 641(M+H)⁺.

Example 63 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-ylthio)phenyl)urea

In the manner described in Example 21C1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)ureafrom Example 57B (200 mg, 0.37 mmol) was reacted with morpholine (96 μL,1.11 mmol), diisopropylethyl amine (193 μL, 1.11 mmol), and tetrabutylammonium iodide (136 mg, 0.37 mmol). The purification and isolationsteps afforded1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-ylthio)phenyl)urea(49 mg, 22% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s, 1H), 9.01 (s,1H), 8.69 (s, 1H), 7.48 (s, 1H), 7.55-7.25 (m, 5H), 6.47 (s, 1H), 4.25(m, 2H), 3.99 (s, 3H), 3.59 (m, 4H), 2.5-2.35 (m, 6H), 2.01 (m, 2H),1.37 (s, 9H); LCMS (ESI) m/z 593 (M+H).

Example 64 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazolin-4-ylthio)phenyl)urea

To a suspension of sodium hydride (11 mg, 0.44 mmol) in anhydroustetrahydrofuran (2 mL) cooled to 0° C., was added compound1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described inExample 44A (117 mg, 0.40 mmol) as a solution in tetrahydrofuran (1 mL)and the mixture stirred at 0° C. for 30 minutes. To this suspension4-chloro-7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazoline from Example41B Step 1 (133 mg, 0.40 mmol) was added and the resulting mixture wasstirred at 0° C. and slowly allowed to reach room temperature. Afterstirring for additional 1 h, the mixture was taken up in ethylacetate/water and extracted. The combined organic layers were dried(MgSO₄) and concentrated under reduced pressure. The residue waspurified by preparative HPLC (Phenomenex phenylhexyl reverse phasecolumn) to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazolin-4-ylthio)phenyl)urea(10.30 mg, 4%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.73 (bs, 1H),9.19 (bs, 1H), 8.70 (s, 1H), 7.85 (s, 1H), 7.53-7.27 (m, 5H), 6.49 (s,1H), 4.32 (bs, 2H), 4.01 (s, 3H), 3.35 (2H), 3.07 (s, 3H), 2.28 (bs,2H), 1.28 (s, 9H); LC-MS (ESI) m/z 586 (M+H)⁺.

Example 65 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(piperidin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea

Example 65A: To 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)ureadescribed in Example 44A (1.07 g, 3.70 mmol) was added4-chloro-6-(2-chloroethoxy)-7-methoxyquinazoline (1.0 g, 3.70 mmol) fromExample 16B according to the procedure described in Example 46 to give1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea(1.54 g, 2.92 mmol, 79%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.59 (s, 1H), 9.02(s, 1H), 8.71 (s, 1H), 7.85 (s, 1H), 7.51 (d, 1H), 7.44 (t, 1H), 7.38(s, 2H), 7.28 (d, 1H), 6.49 (s, 1H), 4.50 (t, 2H), 4.07 (t, 2H), 4.01(s, 3H), 1.29 (s, 9H); LC-MS (ESI) m/z 528 (M+H)⁺.

Example 65B: The urea intermediate from the previous step (200 mg, 0.38mmol) and piperidine (0.112 mL, 1.14 mmol) were reacted as described inExample 57B to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(piperidin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)ureaas a colorless solid (28 mg, 13%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.59(brs, 1H), 9.01 (brs, 1H), 8.69 (s, 1H), 7.86 (s, 1H), 7.25-7.53 (m,5H), 6.49 (s, 1H), 4.25-4.29 (m, 2H), 3.99 (s, 3H), 2.73-2.77 (m, 2H),1.50-1.54 (m, 8H), 1.38-1.40 (m, 2H), 1.27 (s, 9H); LC-MS (ESI) m/z 577(M+H)⁺.

Example 66 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea

The urea intermediate from Example 65A (200 mg, 0.38 mmol) and4-piperidinemethanol (131 mg, 1.14 mmol) were reacted as described inExample 16D to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)-7-methoxyquinazolin-4-ylthio)phenyl)ureaas a colorless solid (28 mg, 12%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.60(brs, 1H), 9.04 (brs, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.26-7.52 (m,5H), 6.49 (s, 1H), 4.41 (m, 1H), 4.27 (m, 2H), 3.99 (s, 3H), 3.24 (m,2H), 2.96-3.00 (m, 2H), 2.74-2.78 (m, 2H), 1.99-2.06 (m, 2H), 1.61-1.65(m, 2H), 1.27 (s, 9H), 1.00-1.15 (m, 2H); LC-MS (ESI) m/z 607 (M+H)⁺.

Example 67 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea

The urea intermediate from Example 65A (200 mg, 0.38 mmol) and N-methylpiperazine (0.126 mL, 1.14 mmol) were reacted as described in Example57B to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)ureaas a colorless solid (49 mg, 22%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.58(brs, 1H), 9.00 (brs, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.26-7.49 (m,5H), 6.49 (s, 1H), 4.25-4.29 (m, 2H), 3.98 (s, 3H), 2.75-2.79 (m, 2H),2.20-2.60 (m, 8H), 2.15 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 592(M+H)⁺.

Example 68 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea

The urea intermediate from Example 65A (200 mg, 0.38 mmol) and1-(2-hydroxyethyl)piperazine (0.139 mL, 1.14 mmol) in the mannerdescribed in Example 57B to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)-7-methoxyquinazolin-4-ylthio)phenyl)ureaas a colorless solid (32 mg, 14%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.58(brs, 1H), 9.00 (brs, 1H), 8.69 (s, 1H), 7.84 (s, 1H), 7.26-7.49 (m,5H), 6.49 (s, 1H), 4.26-4.37 (m, 3H), 3.99 (s, 3H), 3.40-3.50 (m, 2H),2.75-2.79 (m, 2H), 2.30-2.50 (m, 9H), 1.27 (s, 9H); LC-MS (ESI) m/z 622(M+H)⁺.

Example 69 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea

The urea intermediate from Example 65A (200 mg, 0.38 mmol) and1-methylsulfonyl-piperazine (187 mg, 1.14 mmol) in the manner describedin Example 57B to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)ureaas a colorless solid (53 mg, 21%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.58(brs, 1H), 8.99 (brs, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.29-7.51 (m,5H), 6.48 (s, 1H), 4.30-4.32 (m, 2H), 3.99 (s, 3H), 3.14-3.15 (m, 4H),2.86-2.87 (m, 5H), 2.66-2.67 (m, 4H), 1.27 (s, 9H); LC-MS (ESI) m/z 656(M+H)⁺.

Example 70 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-morpholinoethoxy)quinazolin-4-ylthio)phenyl)urea

The urea intermediate from Example 65A (200 mg, 0.38 mmol) andmorpholine (0.099 mL, 1.14 mmol) in the manner described in Example 57Bto afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-morpholinoethoxy)quinazolin-4-ylthio)phenyl)ureaas a colorless solid (29 mg, 13%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.58(brs, 1H), 9.02 (brs, 1H), 8.69 (s, 1H), 7.84 (s, 1H), 7.26-7.49 (m,5H), 6.48 (s, 1H), 4.30-4.32 (m, 2H), 3.99 (s, 3H), 3.60-3.62 (m, 4H),2.80 (m, 2H), 2.49-2.52 (m, 4H), 1.27 (s, 9H); LC-MS (ESI) m/z 579(M+H)⁺.

Example 71 Preparation of1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethoxy]-7-methoxy-quinazolin-4-ylsulfanyl}-phenyl)-urea

The title compound was prepared as described in Example 57B by using1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-ylthio)phenyl)ureafrom Example 65A (200 mg, 0.38 mmol), thiomorpholine 1,1-dioxide (154mg, 1.14 mmol), tetrabutylammonium iodide (140 mg, 0.38 mmol) andN,N′-diisopropylethylamine (135 μL, 0.76 mmol) in N,N′-dimethylformamide(2 mL) to afford1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethoxy]-7-methoxy-quinazolin-4-ylsulfanyl}-phenyl)-urea(56.27 mg, 24%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.59 (s, 1H),9.01 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.52-7.27 (m, 5H), 6.49 (s,1H), 4.30 (bs, 2H), 3.99 (s, 3H), 3.12-3.04 (m, 10H), 1.27 (s, 9H);LC-MS (ESI) m/z 627 (M+H)⁺.

Example 72 Preparation of(1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-ylthio)phenyl)urea)

Example 72A: To a solution of(1-(5-tert-butyl-isoxazol-3-yl)-3-(3-mercapto-phenyl)-urea described inExample 44A (303.02 mg, 1.04 mmol) in THF: DMF (2:1, 6 mL) was added NaH(95%, 28.9 mg, 1.144 mmol), stirred for 5-10 min at ambient temperature.Then (4-chloro-7-(3-chloro-propoxy)-6-methoxy-quinazoline, (300 mg, 1.04mmol) described in Example 27A was added as solution in DMF:THF (2:1).The reaction mixture was then stirred overnight. Completion of thereaction was monitored by LCMS. The reaction mixture was diluted withethyl acetate and washed the ethyl acetate layer with water and brinesuccessively. The organic layer was dried (Na₂SO₄) concentrated todryness to afford the pure1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea(480 mg, 85%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.60 (s,1H), 9.05 (s, 1H), 8.68 (s, 1H), 7.85 (s, 1H), 7.60-7.28 (m, 5H), 6.50(s, 1H), 4.35 (t, 2H), 4.05 (s, 3H), 3.82 (t, 2H), 1.30 (s, 9H); LC-MS(ESI) m/z 542 (M+H)⁺.

Example 72B: To a solution of urea from the previous step (250 mg, 0.461mmol) in DMF (3 mL) was added morpholine (120.5 mg, 1.383 mmol) followedby diisopropyl ethylamine (0.241 mL, 1.383 mmol) and tetrabutyl ammoniumiodide (170.35 mg, 0.461 mmol). The reaction mixture was heated at 60°C. for 15 h. Formation of product was determined by LCMS. The crudereaction was diluted with ethyl acetate (50 mL), washed successivelywith water and brine, dried (MgSO₄) and concentrated in vacuo. The crudereaction mixture was purified by column chromatography (DCM/MeOH) toafford(1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-ylthio)phenyl)urea)(40 mg, 15%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.65 (s, 1H),9.12 (s, 1H), 8.72 (s, 1H), 7.85 (s, 1H), 7.61-7.21 (m, 5H), 6.45 (s,1H), 3.95 (s, 3H), 3.62 (s, 3H), 2.75-2.25 (m, 6H), 2.01 (m, 2H), 1.25(s, 9H); LC-MS (ESI) m/z 593 (M+H)⁺.

Example 73 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea

To a solution of1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-ureafrom Example 72A (200 mg, 0.368 mmol) in DMF (3 mL) was added N-methylpiperazine (0.122 mL, 1.104 mmol) followed by diisopropyl ethylamine(0.192 mL, 1.104 mmol) and tetrabutyl ammonium iodide (136.2 mg, 0.368mmol). The reaction mixture was heated at 60° C. for 24 h. Formation ofthe product was determined by LCMS. The crude reaction mixture waspurified by preparative HPLC (phenomenex phenylhexyl reverse phasecolumn eluted with gradient of solvent A=0.05% HOAc/H₂O and solventB=0.05% HOAc/CH₃CN) to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea(72 mg, 32%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.60 (s, 1H),9.00 (s, 1H), 8.68 (s, 1H), 7.85 (s, 1H), 7.60-7.20 (m, 5H), 6.45 (s,1H), 4.25 (m, 2H), 3.88 (s, 3H), 2.50-2.25 (m, 10H), 2.15 (s, 3H), 1.95(m, 2H), 1.23 (s, 9H); LC-MS (ESI) m/z 606 (M+H)⁺.

Example 74 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea

1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-ureafrom Example 72A (200 mg, 0.368 mmol) and piperidin-4-yl-methanol (127mg, 1.104 mmol) were reacted as described in Example 73. Isolated yieldof1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea(47 mg, 21%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.60 (s, 1H),9.05 (s, 1H), 8.70 (s, 1H), 7.60-7.20 (m, 5H), 6.45 (s, 1H), 4.40 (m,1H), 4.20 (m, 2H), 3.98 (s, 3H), 3.25 (m, 2H), 2.87 (d, 2H), 2.45 (m,2H), 2.10-1.80 (m, 4H), 1.65 (d, 2H), 1.30 (s, 10H), 1.15 (m, 2H); LC-MS(ESI) m/z 621 (M+H)⁺.

Example 75 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea

1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-ureafrom Example 72A (200 mg, 0.368 mmol) and 2-piperazin-1-yl-ethanol (135mL, 1.104 mmol) were reacted as described in Example 73. Isolated yieldof1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea(75 mg, 32%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.80 (s, 1H),9.55 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.60-7.25 (m, 5H), 6.50 (s,1H), 4.40 (s, 1H), 4.25 (m, 2H), 4.00 (s, 3H), 3.45 (m, 2H), 2.50-2.25(m, 12H), 1.95 (m, 2H), 1.25 (s, 9H); LC-MS (ESI) m/z 636 (M+H)⁺.

Example 76 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea

1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-ureafrom Example 72A (200 mg, 0.368 mmol) and piperidine (0.109 mL, 1.104mmol) were reacted as described in Example 73. Isolated yield of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea(57 mg, 26%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.60 (s, 1H),9.05 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.60-7.20 (m, 5H), 6.45 (s,1H), 4.20 (m, 2H), 4.00 (s, 3H), 2.50-2.25 (m, 6H), 1.95 (m, 2H),1.60-1.30 (m, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 591 (M+H)⁺.

Example 77 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-(methylsulfonyl)piperazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea

To a solution of1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-ureafrom Example 72A (200 mg, 0.368 mmol) in DMF (3 mL) was added 1-methanesulfonyl piperazine (181 mg, 1.104 mmol) followed by diisopropylethylamine (0.192 mL, 1.104 mmol) and tetrabutyl ammonium iodide (136.2mg, 0.368 mmol). The reaction mixture was heated at 60° C. for 2 days.Formation of the product was determined by LCMS. The crude reactionmixture was purified by preparative HPLC (phenomenex phenylhexyl reversephase column eluted with gradient of solvent A=0.05% HOAc/H₂O andsolvent B=0.05% HOAc/CH₃CN) to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-(methylsulfonyl)piperazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea(85 mg, 35%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.60 (s, 1H),9.05 (s, 1H), 8.70 (s, 1H), 7.85 (s, 1H), 7.55-7.20 (m, 5H), 6.50 (s,1H), 4.25 (m, 1H), 3.95 (s, 3H), 3.15 (m, 4H), 2.55 (m, 6H), 2.00 (m,2H), 1.30 (s, 9H); LC-MS (ESI) m/z 670 (M+H)⁺.

Example 78 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea

1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-ureafrom Example 72A (200 mg, 0.368 mmol) and pyrrolidine (91 μL 1.104 mmol)were reacted in the manner described in Example 73 to yield1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea(12 mg, 6%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.50 (s, 1H),8.85 (s, 1H), 8.30 (s, 1H), 7.25 (m, 2H), 7.35-7.00 (m, 4H), 6.45 (s,1H), 4.20 (m, 2H), 3.85 (m, 7H), 3.15 (m, 2H), 2.20-1.85 (m, 6H), 1.30(s, 9H); LC-MS (ESI) m/z 577 (M+H)⁺.

Example 79 Preparation of(1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-ylthio)phenyl)urea)

Example 79A: To a solution of1-(5-tert-butyl-isoxazol-3-yl)-3-(3-mercapto-phenyl)-urea (319 mg, 1.098mmol) described in Example 44A in THF:DMF (2:1, 6 mL) was added NaH(95%, 30.5 mg, 1.207 mmol), stirred for 5-10 min at ambient temperature.Then 4-chloro-7-(2-chloro-ethoxy)-6-methoxy-quinazoline from Example 35A(300 mg, 1.098 mmol) was added as a solution in DMF:THF (2:1). Thereaction mixture was then stirred overnight. Completion of the reactionwas monitored by LCMS. The reaction mixture was diluted with ethylacetate and washed the ethyl acetate layer with water and brinesuccessively. The organic layer was dried (Na₂SO₄) concentrated todryness to get the pure compound1-(5-tert-Butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea(550 mg, 95%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.60 (s,1H), 9.05 (s, 1H), 8.68 (s, 1H), 7.85 (s, 1H), 7.55-7.25 (m, 5H), 6.45(s, 1H), 4.50 (m, 2H), 4.05 (m, 5H), 1.25 (s, 9H); LC-MS (ESI) m/z 528(M+H)⁺.

Example 79B: To a solution of the urea from the previous step (100 mg,0.189 mmol) in DMF (2 mL) was added morpholine (49.3 mg, 0.567 mmol)followed by diisopropyl ethylamine (98.7 μL, 0.567 mmol) and tetrabutylammonium iodide (69.8 mg, 0.189 mmol). The reaction mixture was heatedat 60° C. for 3 days. Formation of product was determined by LCMS. Thecrude reaction mixture was purified by preparative HPLC (usingphenylhexyl reverse phase column eluted with gradient of solvent A=0.05%HOAc/H₂O and solvent B=0.05% HOAc/CH₃CN) to afford(1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-morpholino ethoxy)quinazolin-4-ylthio) phenyl)urea) (23 mg, 23%) as a white solid. ¹H NMR(300 MHz, DMSO-d₆) δ 9.85 (s, 1H), 9.70 (s, 1H), 8.70 (s, 1H), 7.85 (s,1H), 7.70-7.25 (m, 5H), 6.50 (s, 1H), 4.40 (s, 2H), 4.05 (s, 3H), 3.85(m, 4H), 2.75-2.35 (m, 6H), 1.35 (s, 9H); LC-MS (ESI) m/z 579 (M+H)⁺.

Example 80 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(piperidin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea

To a solution of1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-ureafrom Example 79A (225 mg, 0.426 mmol) in DMF (3 mL) was added piperidine(0.126 mL, 1.278 mmol) followed by diisopropyl ethylamine (0.222 mL,1.278 mmol) and tetrabutyl ammonium iodide (157.35 mg, 0.426 mmol). Thereaction mixture was heated at 60° C. for 2 days. Formation of productwas determined by LCMS. The crude reaction mixture was purified bypreparative HPLC (using phenylhexyl reverse phase column eluted withgradient of solvent A=0.05% HOAc/H₂O and solvent B=0.05% HOAc/CH₃CN) toafford1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(piperidin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea(42 mg, 17%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.60 (s, 1H),9.20 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.60-7.22 (m, 5H), 6.45 (s,1H), 4.30 (m, 2H), 3.95 (s, 3H), 2.85-2.30 (m, 6H), 1.70-1.30 (m, 6H),1.25 (s, 9H); LC-MS (ESI) m/z 577 (M+H)⁺.

Example 81 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea

To a solution of1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-ureafrom Example 79A (225 mg, 0.426 mmol) in DMF (3 mL) was added 1-methanesulfonyl pyperazine (139.9 mg, 0.852 mmol) followed by diisopropylethylamine (0.222 mL, 1.278 mmol) and tetrabutyl ammonium iodide (157.35mg, 0.426 mmol). The reaction mixture was heated at 60° C. for 3 days.Formation of the product was determined by LCMS. The crude reactionmixture was purified by preparative HPLC (phenomenex phenylhexyl reversephase column eluted with gradient of solvent A=0.05% HOAc/H₂O andsolvent B=0.05% HOAc/CH₃CN) to afford145-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea(47 mg, 17%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.60 (s, 1H),9.05 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.62-7.25 (m, 5H), 6.45 (s,1H), 4.30 (m, 2H), 3.15 (m, 4H), 2.85 (m, 5H), 2.60 (m, 4H), 1.25 (s,9H); LC-MS (ESI) m/z 656 (M+H)⁺.

Example 82 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-(3-hydroxypyrrolidin-1-yl)ethoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea

The intermediate1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-ureafrom Example 79A and pyrrolidin-3-ol were reacted as described inExample 80 to yield1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-(3-hydroxypyrrolidin-1-yl)ethoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea(59 mg, 24%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.55 (s, 1H),8.85 (s, 1H), 8.30 (s, 1H), 7.65-7.50 (m, 2H), 7.35-7.05 (m, 4H), 6.50(s, 1H), 5.05 (s, 1H), 4.45-4.25 (m, 3H), 4.15-3.85 (m, 6H), 3.75-3.65(d, 1H), 3.45 (m, 2H), 2.00 (m, 2H), 1.25 (s, 9H); LC-MS (ESI) m/z 579(M+H)⁺.

Example 83 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea

To a solution of1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-ureafrom Example 79A (225 mg, 0.426 mmol) in DMF (3 mL) was added N-methylpiperazine (0.141 mL, 1.278 mmol) followed by diisopropyl ethylamine(0.222 mL, 1.278 mmol) and tetrabutyl ammonium iodide (157.35 mg, 0.426mmol). The reaction mixture was heated at 60° C. for 24 h. Formation ofthe product was determined by LCMS. The crude reaction mixture waspurified by preparative HPLC (using phenylhexyl reverse phase columneluted with gradient of solvent A=0.05% HOAc/H₂O and solvent B=0.05%HOAc/CH₃CN) to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea(21 mg, 8.3%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.60 (s,1H), 9.05 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.60-7.25 (m, 5H), 6.45(s, 1H), 4.35 (m, 2H), 4.00 (m, 3H), 2.80-2.25 (m, 10H), 2.15 (s, 3H),1.25 (s, 9H); LC-MS (ESI) m/z 592 (M+H)⁺.

Example 84 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea

To the intermediate1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea(225 mg, 0.426 mmol) from Example 79A was added 2-piperazin-1-yl-ethanol(0.157 mL, 1.278 mmol) followed by diisopropyl ethylamine (1.3 mmol) andtetrabutyl ammonium iodide (0.43 mmol). The reaction mixture was heatedat 60° C. for 3 days. Formation of product was determined by LCMS. Thecrude reaction mixture was purified by preparative HPLC (usingphenylhexyl reverse phase column eluted with gradient of solvent A=0.05%HOAc/H₂O and solvent B=0.05% HOAc/CH₃CN) to afford145-tert-butylisoxazol-3-yl)-3-(3-(7-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea(34 mg, 13%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.60 (s, 1H),9.05 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.60-7.20 (m, 5H), 6.45 (s,1H), 4.45-4.25 (m, 3H), 4.00 (s, 3H), 3.45 (m, 2H), 2.80-2.30 (m, 12H),1.25 (s, 9H); LC-MS (ESI)m/z 622 (M+H)⁺.

Example 85 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea

To the intermediate1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea(225 mg, 0.426 mmol) from Example 79A was added pyrrolidine (0.105 mL,1.278 mmol) in the manner described in Example 80 to yield1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea(41 mg, 18%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.55 (s, 1H),8.85 (s, 1H), 8.30 (s, 1H), 7.65-7.50 (m, 2H), 7.35-7.05 (m, 4H), 6.50(s, 1H), 4.30 (m, 2H), 4.00-3.75 (m, 7H), 2.55 (m, 2H), 1.98 (m, 4H),1.30 (s, 9H); LC-MS (ESI)m/z 563 (M+H)⁺.

Example 86 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea

The intermediate1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea(225 mg, 0.426 mmol) from Example 79A and piperidin-4-yl-methanol (147mg, 1.278 mmol) were reacted using the procedure described in Example 80to yield of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea(61 mg, 24%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.55-10.05(m, 2H), 8.68 (s, 1H), 7.85 (s, 1H), 7.65-7.20 (m, 5H), 6.50 (s, 1H),4.50 (s, 1H), 4.30 (s, 2H), 4.02 (s, 3H), 3.25 (m, 2H), 3.00 (m, 2H),2.80-2.65 (m, 4H), 2.05 (m, 2H), 1.70-1.50 (m, 2H), 1.30 (s, 10H); LC-MS(ESI)m/z 607 (M+H)⁺.

Example 87 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea

The title compound was prepared from1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described inExample 44A (146 mg, 0.5 mmol) and4-chloro-6-(2-methoxyethoxy)quinazoline from Example 40A (119 mg, 0.5mmol) using the procedure described in Example 46 to give1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea(160 mg, 0.32 mmol, 64%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.61 (s, 1H), 9.03(s, 1H), 8.76 (s, 1H), 7.96-7.85 (m, 2H), 7.70 (dd, 1H), 7.58-7.42 (m,3H), 7.30 (d, 1H), 6.50 (s, 1H), 4.37-4.30 (m, 2H), 3.79-3.74 (m, 2H),3.38 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 494 (M+H)⁺.

Example 88 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(methylsulfonyl)ethoxy)quinazolin-4-ylthio)phenyl)urea

Example 88A Step 1: 6-(2-Chloroethoxy)-4-hydroxy-7-methoxyquinazoline(1.12 g, 4.4 mmol) from Example 16A was reacted using the proceduredescribed in Example 41B Step 1 to give4-hydroxy-7-methoxy-6-(2-(methylthio)ethoxy)quinazoline (1.02 g, 3.83mmol, 87%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.09 (br s, 1H), 7.99 (s, 1H),7.46 (s, 1H), 7.14 (s, 1H), 4.24 (t, 2H), 3.91 (s, 3H), 3.89 (t, 2H),2.20 (s, 3H); LC-MS (ESI) m/z 267 (M+H)⁺.

Example 88A Step 2:4-Hydroxy-7-methoxy-6-(2-(methylthio)ethoxy)quinazoline (800 mg, 3.0mmol) was reacted using the procedure described in Example 41B Step 2 togive 4-hydroxy-7-methoxy-6-(2-(methylsulfonyl)ethoxy)quinazoline (880mg, 2.95 mmol, 98%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.13 (br s, 1H), 8.02(s, 1H), 7.51 (s, 1H), 7.18 (s, 1H), 4.43 (t, 2H), 3.92 (s, 3H), 3.68(t, 2H), 3.17 (s, 3H); LC-MS (ESI) m/z 299 (M+H)⁺.

Example 88A Step 3:4-Hydroxy-7-methoxy-6-(2-(methylsulfonyl)ethoxy)quinazoline (880 mg,2.95 mmol) was reacted using the procedure described in Example 41B Step3, to give 4-chloro-7-methoxy-6-(2-(methylsulfonyl)ethoxy)quinazoline(405 mg, 1.28 mmol, 43%). LC-MS (ESI) m/z 317 (M+H)⁺.

Example 88B: 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)ureadescribed in Example 44A (92 mg, 0.32 mmol) was treated with cesiumcarbonate (113 mg, 0.35 mmol) in anhydrous tetrahydrofuran (2 mL) andthe suspension stirred at 40° C. for 20 minutes.4-Chloro-7-methoxy-6-(2-(methylsulfonyl)ethoxy)quinazoline from theprevious step (100 mg, 0.32 mmol) was carefully added in portions andthe resulting mixture heated at 40° C. for 2 h. Cesium carbonate wasfiltered off, the filtrate concentrated under reduced pressure and theresidue purified by preparative HPLC (Phenomenex phenylhexyl reversephase column) to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(methylsulfonyl)ethoxy)quinazolin-4-ylthio)phenyl)urea(36.88 mg, 20%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.59 (s, 1H),9.01 (s, 1H), 8.72 (s, 1H), 7.85 (s, 1H), 7.53-7.40 (m, 4H), 7.30-7.28(d, 1H), 6.49 (s, 1H), 4.59-4.56 (m, 2H), 4.00 (s, 3H), 3.78-3.74 (m,2H), 3.20 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 572 (M+H)⁺.

Example 89 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(2-chloro-6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

To a slurry of sodium hydride (7.5 mg, 0.3 mmol) in DMF (3 mL) was added1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described inExample 44A (90 mg, 0.3 mmol), and the solution stirred at roomtemperature When gas evolution ceased,2,4-dichloro-6,7-dimethoxyquinazoline (78 mg, 0.3 mmol) was added andthe solution heated at 50° C. overnight, cooled to room temperature, anddiluted with H₂O. The mixture was extracted with EtOAc, the organiclayer washed with aqueous sat. NaHCO₃ and brine, dried over MgSO₄,filtered and concentrated in vacuo. The crude solid was purified by HPLCto give1-(5-tert-butylisoxazol-3-yl)-3-(3-(2-chloro-6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(20 mg, 0.04 mmol, 13%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.79 (s, 1H), 9.53(s, 1H), 7.90 (s, 1H), 7.62 (d, 1H), 7.44 (t, 1H), 7.36 (s, 2H), 7.27(d, 1H), 6.49 (s, 1H), 4.00 (s, 6H), 1.28 (s, 9H); LC-MS (ESI) m/z 514(M+H)⁺.

Example 90 Preparation of1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-quinazolin-4-ylsulfanyl}-phenyl)-urea

Example 90A Step 1: Methyl 5-hydroxy-2-nitrobenzoate (4.37 g, 22.17mmol, prepared as previously described), and 1-bromo-3-chloropropane(6.58 mL, 66.5 mmol) were reacted using the procedure described inExample 40A Step 3 to give methyl 5-(3-chloropropoxy)-2-nitrobenzoate(5.70 g, 20.8 mmol, 94%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.14 (d, 1H), 7.33(d, 1H), 7.30 (dd, 1H), 4.27 (dt, 2H), 3.86 (s, 3H), 3.68 (t, 2H), 2.21(t, 2H); LC-MS (ESI) m/z 274 (M+H)⁺.

Example 90A Step 2: Methyl 5-(3-chloropropoxy)-2-nitrobenzoate (5.7 g,20.8 mmol) was reacted using the procedure described in Example 40A Step4 to give methyl 2-amino-5-(3-chloropropoxy)benzoate (4.83 mg, 19.8mmol, 95%). LC-MS (ESI) m/z 244 (M+H)⁺.

Example 90A Step 3: Methyl 2-amino-5-(3-chloropropoxy)benzoate (4.83 g,19.8 mmol) was reacted using the procedure described in Example 40A Step5. The product was purified by column chromatography (25-100%EtOAc/hexanes) to give 6-(3-chloropropoxy)-4-hydroxyquinazoline (1.04 g,4.3 mmol, 22%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.20 (br s, 1H), 7.99 (s,1H), 7.62 (d, 1H), 7.52 (d, 1H), 7.44 (dd, 1H), 4.17 (dt, 2H), 3.82 (t,2H), 2.22 (t, 2H); LC-MS (ESI) m/z 239 (M+H)⁺.

Example 90A Step 4: 6-(3-chloropropoxy)-4-hydroxyquinazoline (540 mg,2.26 mmol) was reacted using the procedure described in Example 40A Step6 to give 4-chloro-6-(3-chloropropoxy)quinazoline (485 mg, 1.9 mmol,83%). LC-MS (ESI) m/z 258 (M+H)⁺.

Example 90B: Using the procedure described in Example 46,1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described inExample 44A (181 mg, 0.62 mmol) was reacted with4-chloro-6-(3-chloropropoxy)-quinazoline from the previous step (160 mg,0.62 mmol) to give1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea(230 mg, 0.45 mmol, 72%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.60 (s, 1H), 9.02(s, 1H), 8.76 (s, 1H), 7.94 (d, 1H), 7.86 (s, 1H), 7.72 (d, 1H),7.58-7.42 (m, 3H), 7.30 (d, 1H), 6.49 (s, 1H), 4.33 (t, 2H), 3.87 (t,2H), 2.32-2.25 (m, 2H), 1.28 (s, 9H); LC-MS (ESI) m/z 512 (M+H)⁺.

Example 90C: The title compound was prepared as described in Example 57Bby using1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)ureafrom the previous step (230 mg, 0.45 mmol), thiomorpholine 1,1-dioxide(182 mg, 1.35 mmol), tetrabutylammonium iodide (166 mg, 0.45 mmol) andN,N′-diisopropylethylamine (160 μL, 0.89 mmol) in N,N′-dimethylformamide(3 mL) to afford1-(5-tert-Butyl-isoxazol-3-yl)-3-(3-{6-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-quinazolin-4-ylsulfanyl}-phenyl)-urea(117 mg, 43%) as solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.61 (s, 1H), 9.03(s, 1H), 8.75 (s, 1H), 7.94-7.86 (m, 2H), 7.68 (d, 1H), 7.51-7.41 (m,3H), 7.30 (d, 1H), 6.49 (s, 1H), 4.26-4.23 (m, 2H), 3.11 (bs, 4H), 2.95(bs, 4H), 2.71-2.67 (m, 2H), 2.00-1.96 (m, 2H), 1.27 (s, m 9H); LC-MS(ESI) m/z 611 (M+H)⁺.

Example 91 Preparation of1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethoxy]-7-methoxy-quinazolin-4-yloxy}-phenyl)-urea

The title compound was prepared as described in Example 57B by usingcompound1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)ureafrom Example 16C (200 mg, 0.39 mmol), thiomorpholine 1,1-dioxide (158mg, 1.17 mmol), tetrabutylammonium iodide (144 mg, 0.39 mmol) andN,N′-diisopropylethylamine (139 μL, 0.78 mmol) in N,N′-dimethylformamide(2 mL) to afford1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethoxy]-7-methoxy-quinazolin-4-yloxy}-phenyl)-urea(52.75 mg, 23%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s, 1H),9.00 (s, 1H), 8.56 (s, 1H), 7.61 (d, 2H), 7.40-7.37 (m, 2H), 7.25 (d,1H), 6.97 (d, 1H), 6.47 (s, 1H), 4.31 (m, 2H), 4.00 (s, 3H), 3.10-3.03(m, 10H), 1.27 (s, 9H); LC-MS (ESI) m/z 611 (M+H)⁺.

Example 92 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-(5-{[2-(methylsulfonyl)ethylamino]methyl}furan-2-yl)quinazolin-4-yloxy]phenyl}urea

Example 92A Step 1: A mixture of 2-amino-5-iodobenzoic acid (9.00 g,34.2 mmol) and formamidine acetate (18.00 g, 173 mmol) in acetic acid(50 mL) was heated at 130° C. for 3 hours. After it was cooled down toroom temperature, it was quenched with water, filtered, washed withwater, and dried under vacuum with P₂O₅ to afford6-iodoquinazolin-4(3H)-one as solid (9.289 g, 99.8%). ¹H NMR (300 MHz,DMSO-d₆) δ 8.38 (d, 1H), 8.13 (s, 1H), 8.09 (dd, 1H), 7.46 (d, 1H);LC-MS (ESI) m/z 273 (M+H)⁺.

Example 92A Step 2: To a mixture of 6-iodoquinazolin-4(3H)-one (1.70 g,6.25 mmol) in SOCl₂ (10 mL) was dropped a few drops of DMF, and then itwas heated at 90° C. for 5 hours. After excess SOCl₂ was removed underreduced pressure, to it was added CH₂Cl₂ and water, and neutralized withsaturated NaHCO₃ solution. The aqueous was extracted with CH₂Cl₂ threetimes. Extracts were dried over MgSO₄ and concentrated under reducedpressure to afford 4-chloro-6-iodoquinazoline as solid (1.266 g, 70%).¹H NMR (300 MHz, CDCl₃) δ 9.07 (s, 1H), 8.67 (d, 1H), 8.22 (dd, 1H),7.81 (d, 1H).

Example 92A Step 3: A mixture of1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (0.413 g, 1.5mmol) from Example 1A, 4-chloro-6-iodoquinazoline (0.436 g, 1.5 mmol),and Cs₂CO₃ (0.489 g, 1.5 mmol) in isopropanol (10 mL) was heated at 50°C. for 2 hours. It was quenched with water and extracted with CH₂Cl₂.Extracts were dried over MgSO₄ and concentrated under reduced pressure.It was purified by silica gel chromatography with EtOAc/hexane as eluantto afford1-(5-tert-butylisoxazol-3-yl)-3-[3-(6-iodoquinazolin-4-yloxy)phenyl]ureaas solid (0.551 g, 69%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.66 (s, 1H), 9.08(s, 1H), 8.84 (s, 1H), 8.78 (m, 1H), 8.40 (dd, 1H), 7.87 (d, 1H), 7.67(d, 1H), 7.49 (t, 1H), 7.38 (d, 1H), 7.09 (d, 1H), 6.55 (s, 1H), 1.35(s, 9H); LC-MS (ESI) m/z 530 (M+H)⁺.

Example 92B: A mixture of1-(5-tert-butylisoxazol-3-yl)-3-[3-(6-iodoquinazolin-4-yloxy)phenyl]ureafrom the previous step (0.21 g, 0.4 mmol), 5-formylfuran-2-ylboronicacid (0.07 g, 0.51 mmol), bis(triphenylphosphine)palladium(II)dichloride(0.035 g, 0.05 mmol), and 1.0 M Na₂CO₃ solution (3 mL) in EtOH (2 mL)and 1,2-dimethoxyethane (3 mL) was heated at 55° C. for 1 hour. It wasquenched with water and extracted with CH₂Cl₂. Extracts were dried overMgSO₄ and concentrated under reduced pressure. It was purified by silicagel chromatography with 30-60% EtOAc/hexane as eluants to afford1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-(5-formylfuran-2-yl)quinazolin-4-yloxy]phenyl}ureaas solid (0.172 g, 87%). ¹H NMR (300 MHz, CDCl₃) δ 9.75 (s, 1H), 9.53(br, 1H), 8.80 (d, 1H), 8.78 (s, 1H), 7.32 (dd, 1H), 8.07 (d, 1H), 7.67(m, 2H), 7.34-7.54 (m, 3H), 7.07 (d, 1H), 7.01 (d, 1H), 5.94 (s, 1H),1.32 (s, 9H); LC-MS (ESI) m/z 498 (M+H)⁺.

Example 92C Step 1. To a 1.0 M solution of BH₃.THF in THF (40 mL) at 40°C. was added 2-(methylsulfonyl)acetonitrile (2.383 g, 20 mmol) inseveral small portions. After addition it was stirred at roomtemperature overnight. It was poured into MeOH (40 mL) and concentratedunder reduced pressure. To the residue was added MeOH (60 mL) and 1.0 MHCl/Et₂O solution (30 mL), and then it was heated to reflux for 1 hour.After it was concentrated under reduced pressure to about 40 mL, to itwas added a 7 N NH₃/MeOH solution until it was basic. It wasconcentrated under reduced pressure to dryness and dried under vacuum,to afford 2-(methylsulfonyl)ethanamine as solid (2.41 g). It was used innext step without further purification.

Example 92C Step 2. To a mixture of1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-(5-formylfuran-2-yl)quinazolin-4-yloxy]phenyl}urea(0.17 g. 0.34 mmol), 2-(methylsulfonyl)ethanamine (0.15 g. 1.2 mmol),and MgSO₄ in CH₂Cl₂ was added acetic acid (4 drops), followed by MeOH (1mL). After the mixture was stirred at room temperature for 1 hour,NaBH(OAc)₃ (0.212 g, 1 mmol) was added. After stirring the mixture atroom temperature for more 2 hours, more NaBH(OAc)₃ (0.212 g, 1 mmol) wasadded and stirred at room temperature overnight. The reaction wasquenched with water, basified with saturated NaHCO₃, and extracted withCH₂Cl₂. The extracts were dried over MgSO₄ and concentrated underreduced pressure. The crude product was purified by silica gelchromatography with 2-6% MeOH/EtOAc as eluants to afford1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-(5-{[2-(methylsulfonyl)ethylamino]methyl}furan-2-yl)quinazolin-4-yloxy]phenyl}ureaas solid (0.052 g, 25%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.59 (s, 1H), 9.02(s, 1H), 8.70 (s, 1H), 8.52 (s, 1H), 8.38 (d, 1H), 8.03 (d, 1H), 7.61(s, 1H), 7.43 (t, 1H), 7.31 (d, 1H), 7.23 (d, 1H), 7.03 (d, 1H), 6.48(m, 2H), 3.83 (br, 2H), 3.24 (t, 2H), 3.02 (s, 3H), 2.97 (br, 2H), 1.27(s, 9H); LC-MS (ESI) m/z 605 (M+H)⁺.

Example 93 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-[3-(6-morpholinoquinazolin-4-yloxy)phenyl]urea

A mixture of1-(5-tert-butylisoxazol-3-yl)-3-[3-(6-iodoquinazolin-4-yloxy)phenyl]ureafrom Example 92A (0.225 g, 0.425 mmol), morpholine (0.5 mL), xamtphhos(0.087 g, 0.15 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.046g, 0.05 mmol), and Cs₂CO₃ (0.489 g, 1.5 mmol) in 1,2-dimethoxyethane (8mL) was heated at 70° C. for 4 hours. It was quenched with water andextracted with CH₂Cl₂. Extracts were dried over MgSO₄ and concentratedunder reduced pressure. It was purified by silica gel chromatophraphywith 30-100% EtOAc/hexane and 5% MeOH/EtOAc as eluants, and bypreparative HPLC (C₁₈) with 60-80% CH₃CN/H₂O (0.05% AcOH) to afford1-(5-tert-butylisoxazol-3-yl)-3-[3-(6-morpholinoquinazolin-4-yloxy)phenyl]ureaas a solid (0.007 g, 3.4%). ¹H NMR (300 MHz, CD₃CN) δ 9.48 (br, 1H),8.39 (s, 1H), 7.78 (m, 4H), 7.67 (dd, 1H), 7.44 (m, 3H), 7.03 (d, 1H),3.76 (t, 4H), 3.23 (t, 4H), 1.11 (s, 9H); LC-MS (ESI) m/z 489 (M+H)⁺.

Example 94 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-{3-[7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-yloxy]phenyl}urea

Example 94A Step 1: To a solution of 3,5-dimethoxyaniline (15.00 g, 97.9mmol) in diethyl ether (300 mL) was added 1.0 M HCl solution in diethylether (100 mL). A white solid was formed, filtered, washed with Et₂O,and dried under vacuum. The solid was mixed with oxalyl chloride (30 mL)and it was heated at 165° C. for 30 minutes to form a green solid. Theexcess oxalyl chloride was evaporated under reduced pressure. To thesolid was added MeOH (150 mL) and heated to reflux. After it was cooleddown to room temperature, it was filtered, washed with MeOH, and driedunder vacuum, to afford 4,6-dimethoxyindoline-2,3-dione as a solid(20.285 g, 100%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.92 (s, 1H), 6.17 (d,1H), 6.01 (d, 1H), 3.88 (s, 3H), 3.86 (s, 3H); LC-MS (ESI) m/z 208(M+H)⁺.

Example 94A Step 2: To a mixture of 4,6-dimethoxyindoline-2,3-dione(20.28 g, 97.9 mmol) in 30% NaOH solution (100 mL) at 100° C. wascarefully dropped a 50% H₂O₂ solution. It was heated at 100° C. for 20minutes. It was cooled down and neutralized by concentrated HCl to pH 8,followed by acetic acid to pH 5 to form a solid. It was filtered, washedwith water, and dried under vacuum with P₂O₅ to afford2-amino-4,6-dimethoxybenzoic acid as a yellow solid (15.034 g, 78%). ¹HNMR (300 MHz, DMSO-d₆) δ 6.00 (d, 1H), 5.85 (d, 1H), 3.83 (s, 3H), 3.77(s, 3H), 3.41 (br, 2H); LC-MS (ESI) m/z 198 (M+H)⁺.

Example 94A Step 3: To a mixture of 2-amino-4,6-dimethoxybenzoic acid(7.888 g, 40 mmol) in MeOH (40 mL) and THF (40 mL) at room temperaturewas dropped 2.0 M solution of (trimethylsilyl)diazomethane in diethylether. The mixture was stirred at room temperature overnight. After thesolvent was evaporated under reduced pressure, water and EtOAc was addedto the residue. The organic layer was separated, dried (MgSO₄) andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography with 20-40% EtOAc/hexane as eluants to affordmethyl 2-amino-4,6-dimethoxybenzoate as a solid (6.462 g, 76%). ¹H NMR(300 MHz, CDCl₃) δ 5.83 (d, 1H), 5.78 (d, 1H), 5.53 (br, 2H), 3.86 (s,3H), 3.80 (s, 3H), 3.77 (s, 3H); LC-MS (ESI) m/z 212 (M+H)⁺.

Example 94A Step 4: A mixture of methyl 2-amino-4,6-dimethoxybenzoate(6.46 g, 30.6 mmol), formamidine acetate (15.92 g, 153 mmol) in2-methoxyethanol (50 mL) was heated at 130° C. for 4 hours. After thesolvent was removed under reduced pressure, the reaction was quenchedwith water, filtered, washed with water, and dried under vacuum withP₂O₅ to afford 5,7-dimethoxyquinazolin-4(3H)-one as a solid (4.805 g,76%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.7 (br, 1H), 7.98 (s, 1H), 6.72 (d,1H), 6.60 (d, 1H), 3.92 (s, 3H), 3.88 (s, 3H); LC-MS (ESI) m/z 207(M+H)⁺.

Example 94A Step 5: To a mixture of 5,7-dimethoxyquinazolin-4(3H)-one(4.80 g, 23.3 mmol) in pyridine (50 mL) at room temperature was slowlyadded MgBr₂ (4.29 g, 23.3 mmol). It was heated to reflux for 1.5 hour.After solvent was evaporated under reduced pressure, to the residue wasadded a solution of AcOH (10 mL) in water (50 mL). A solid wasprecipitated. It was filtered, washed with water, and dried under vacuumwith P₂O₅ to afford 5-hydroxy-7-methoxyquinazolin-4(3M-one as solid(4.398 g, 98%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.95 (br, 1H), 8.08 (s,1H), 6.63 (s, 1H), 6.50 (s, 1H), 3.85 (s, 3H); LC-MS (ESI) m/z 193(M+H)⁺.

Example 94A Step 6: To a suspension of5-hydroxy-7-methoxyquinazolin-4(3H)-one (4.395 g, 22.9 mmol) in DMF (50mL) at 0° C. was added 1.0 M solution of lithiumbis(trimethylsilyl)amide in THF (55 mL, 55 mmol). After it was stirredat room temperature for 1 hour, it was cooled again with an ice-waterbath and to it was added chloromethyl pivalate (4.14 g, 27.5 mmol).After it was stirred at room temperature for another hour, it wasquenched with a solution of AcOH (10 mL) in water (150 mL) and extractedwith CH₂Cl₂. Extracts were dried over MgSO₄ and concentrated to affordthe (5-hydroxy-7-methoxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate solid(5.674 g, 81%). ¹H NMR (300 MHz, CDCl₃) δ 11.36 (s, 1H), 8.16 (s, 1H),6.69 (d, 1H), 6.51 (d, 1H), 5.88 (s, 2H), 3.89 (s, 3H), 1.21 (s, 9H);LC-MS (ESI) m/z 307 (M+H)⁺.

Example 94A Step 7: To a solution of(5-hydroxy-7-methoxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate (2.50 g,8.16 mmol), tetrahydro-4H-pyran-4-ol (1.02 g, 10 mmol), and Ph₃P (3.41g, 13 mmol) in CH₂Cl₂ (40 mL) at 0° C. was added di t-butylazodicarboxylate (3.993 g, 13 mmol). It was stirred at room temperaturefor 2 hour. After solvent was evaporated under reduced pressure, to theresidue was added 7 N NH₃/MeOH (80 mL) and stirred at room temperatureovernight. A solid was precipitated. It was filtered, washed with MeOH,and dried under vacuum to afford7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4(3H)-one as solid(1.091 g, 76%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.6 (br, 1H), 7.98 (s, 1H),6.74 (d, 1H), 6.69 (d, 1H), 4.79 (m, 1H), 3.97 (m, 2H), 3.91 (s, 3H),3.57 (m, 2H), 1.98 (m, 2H), 1.74 (m, 2H); LC-MS (ESI) m/z 277 (M+H)⁺.

Example 94A Step 8: A mixture of7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4(3H)-one (0.60 g,2.17 mmol), POCl₃ (0.5 mL), and N,N-diisopropylethylamine (1.5 mL) inClCH₂CH₂Cl (6 mL) was heated at 100° C. for 4 hours. After the solventand reagents were evaporated under reduced pressure, toluene was addedto the residue, and the solution was evaporated under reduced pressure.The residue was dried under vacuum to afford4-chloro-7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazoline as a brownsolid. LC-MS (ESI) m/z 295 (M+H)⁺.

Example 94B: Using the procedure described in Example 92A Step 3, using1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (0.193 g, 0.7mmol) from Example 1A,4-chloro-7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazoline from theprevious step (0.212 g, 0.72 mmol), and Cs₂CO₃ (0.326 g, 1 mmol) inisopropanol (10 mL) at 60° C. for 4 hours, to afford1-(5-tert-butylisoxazol-3-yl)-3-{3-[7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-yloxy]phenyl}ureaas solid (0.104 g, 28%). ¹H NMR (300 MHz, CDCl₃) δ 9.4 (s, 1H), 8.58 (s,1H), 7.94 (s, 1H), 7.56 (s, 1H), 7.37 (d and s, 2H), 6.95 (d and s, 2H),6.59 (s, 1H), 5.89 (s, 1H), 4.76 (m 1H), 3.99 (m, 2H), 3.96 (s, 3H),3.66 (m, 2H), 2.06 (m, 2H), 1.95 (m, 2H), 1.33 (s, 9H); LC-MS (ESI) m/z534 (M+H)⁺.

Example 95 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)urea

Example 95A Step 1: A stirred mixture of7-(benzyloxy)-6-methoxyquinazolin-4-ol (5.10 g, 18.09 mmol) andphosphorous oxychloride (10 mL, 109 mmol) in dry toluene (30 mL), washeated to 120° C. for 2 h. After cooling to room temperature the mixturewas concentrated under reduced pressure. The residue was dissolved inethyl acetate (200 mL) and washed with sat aqueous NaHCO₃ solution(2×100 mL). The organic layer was separated and dried over MgSO₄ thenconcentrated under reduced pressure to afford7-(benzyloxy)-4-chloro-6-methoxyquinazoline as a cream solid (3.89 g,72%) which was taken into the next step without further purification. ¹HNMR (300 MHz, CDCl₃) δ 8.85 (s, 1H), 7.49 (m, 2H), 7.33-7.43 (m, 5H),5.33 (s, 2H), 4.07 (s, 3H); LC-MS (ESI) m/z 301 (M+H)⁺.

Example 95A Step 2: To a stirred solution of 3-aminophenol (1.41 g,12.93 mmol) in dry tetrahydrofuran (70 mL) at room temperature, wasadded cesium carbonate (6.32 g, 19.39 mmol). After stirring for afurther 75 mins, added 7-(benzyloxy)-4-chloro-6-methoxyquinazoline fromthe previous step (3.89 g, 12.93 mmol) in one portion and the reactionmixture was heated at 75° C. for 24 h. After cooling to room temperaturethe mixture was concentrated under reduced pressure. The residue waspartitioned between water (200 mL) and a mixture of dichloromethane (160mL) and 2-propanol (60 mL). The mixture was filtered through a celiteplug and the organic layer was separated and dried over MgSO₄ andconcentrated under reduced pressure. Trituration with diethyl ether,followed by filtration and drying under reduced pressure, afforded3-(7-(benzyloxy)-6-methoxyquinazolin-4-yloxy)aniline as a cream solid(3.57 g, 74%) which was taken into the next step without furtherpurification. ¹H NMR (300 MHz, CDCl₃) δ 8.62 (s, 1H), 7.21-7.55 (m, 8H),6.57-6.63 (m, 3H), 5.33 (s, 2H), 4.03 (s, 3H), 3.73 (brs, 2H); LC-MS(ESI) m/z 374 (M+H)⁺.

Example 95A Step 3: A stirred mixture of3-(7-(benzyloxy)-6-methoxyquinazolin-4-yloxy)aniline from the previousstep (2.52 g, 6.76 mmol) and palladium (10% wt on activated carbon) (200mg) in ethanol (100 mL), under 1 atmosphere of hydrogen gas, was heatedat 50° C. for 45 mins. The reaction mixture was filtered through acelite plug and concentrated under reduced pressure. The residue waspurified via silica gel chromatography eluting with 1% to 10% methanolin dichloromethane to afford 4-(3-aminophenoxy)-6-methoxyquinazolin-7-olas a colorless solid (840 mg, 44%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.73(brs, 1H), 8.47 (s, 1H), 7.50 (s, 1H), 7.21 (s, 1H), 7.08 (m, 1H),6.35-6.50 (m, 3H), 5.28 (brs, 2H), 3.97 (s, 3H); LC-MS (ESI) m/z 284(M+H)⁺.

Example 95B: A stirred mixture of4-(3-aminophenoxy)-6-methoxyquinazolin-7-ol from the previous step (500mg, 1.77 mmol) and phenyl 5-tert-butylisoxazol-3-ylcarbamate (460 mg,1.77 mmol) in dry N,N-dimethylformamide (10 mL) was heated at 60° C. for5 h. After cooling to room temperature the mixture was concentratedunder reduced pressure. The residue was triturated with diethyl etherand filtered and dried under reduced pressure to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)ureaas a cream solid (650 mg, 82%) which did not require furtherpurification. ¹H NMR (300 MHz, DMSO-d₆) δ 10.78 (brs, 1H), 9.58 (brs,1H), 9.00 (brs, 1H), 8.48 (s, 1H), 7.55-7.57 (m, 2H), 7.40 (m, 1H),7.24-7.26 (m, 2H), 6.97 (m, 1H), 6.48 (s, 1H), 3.99 (s, 3H), 1.28 (s,9H); LC-MS (ESI) m/z 450 (M+H)⁺.

Example 96 Preparation of(S)-1-(5-tert-Butyl-isoxazol-3-yl)-3-{3-[6-methoxy-7-(pyrrolidin-3-yloxy)-quinazolin-4-yloxy]-phenyl}-urea(S)-tert-butyl3-(4-(3-(3-(5-tert-butylisoxazol-3-yl)ureido)phenoxy)-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylate

Example 96A: A solution of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)ureafrom Example 95B (50 mg, 0.111 mmol),(R)-3-hydroxy-1-tert-butoxycarbonylpyrrolidine (31 mg, 0.167 mmol),triphenylphosphine (44 mg, 0.167 mmol) and diisopropylazodicarboxylate(34 mg, 0.167 mmol) in dry tetrahydrofuran (1 mL) was stirred at roomtemperature for 15 h. The reaction mixture was partitioned betweenaqueous 1M sodium hydroxide solution (20 mL) and 10% methanol indichloromethane (50 mL) and the organic layer was separated and washedwith brine (50 mL), dried over MgSO₄, and concentrated under reducedpressure. The residue was purified via silica gel chromatography elutingwith 100% dichloromethane to 10% methanol in dichloromethane to afford(S)-tert-butyl3-(4-(3-(3-(5-tert-butylisoxazol-3-yl)ureido)phenoxy)-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylateas a colorless oil (35 mg, 51%). ¹H NMR (300 MHz, CDCl₃) δ 9.30 (brs,1H), 8.62 (s, 1H), 8.30 (brs, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 7.26-7.39(m, 2H), 7.00 (m, 1H), 5.95 (s, 1H), 5.12 (s, 1H), 4.02 (s, 3H),3.50-3.80 (m, 5H), 2.20-2.40 (m, 2H), 1.50 (s, 9H), 1.30 (s, 9H); LC-MS(ESI) m/z 619 (M+H)⁺.

Example 96B: A solution of (S)-tert-butyl3-(4-(3-(3-(5-tert-butylisoxazol-3-yl)ureido)phenoxy)-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylatefrom the previous step (35 mg, 0.0566 mmol) and hydrochloric acid (0.1mL of a 4N solution in 1,4-dioxane, 0.40 mmol) in dry dichloromethane(0.01 mL) was stirred at room temperature for 2 h. Concentrated underreduced pressure to afford(S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)ureadihydrochloride as a colorless solid (22 mg, 67%), which did not requirefurther purification. ¹H NMR (300 MHz, MeOH-d₄) δ 9.02 (brs, 1H), 7.82(s, 1H), 7.73 (brs, 1H), 7.54 (s, 1H), 7.41 (m, 1H), 7.29 (m, 1H), 7.06(m, 1H), 6.32 (s, 1H) 5.56 (brs, 1H), 4.04 (s, 3H), 3.50-3.85 (m, 5H),2.50-2.60 (m, 2H), 1.35 (s, 9H); LC-MS (ESI) m/z 519 (M+H)⁺.

Example 97 Preparation of(S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(1-methylpyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)ureamono acetate

A solution of(S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)ureadihydrochloride from Example 96B (100 mg, 0.193 mmol) and formaldehyde(0.08 mL of a 37 wt % solution in water, 0.987 mmol) in a mixture of dry1,2-dichloroethane (1.5 mL) and dry N,N-dimethylformamide (0.8 mL) wasstirred at room temperature for 20 mins. Sodium triacetoxyborohydride(135 mg, 0.640 mmol) was added in one portion and stirring continued fora further 45 mins. The reaction mixture was partitioned between aqueous1M sodium hydroxide solution (20 mL) and 10% methanol in dichloromethane(50 mL) and the organic layer was separated and washed with brine (50mL), dried over MgSO₄, and concentrated under reduced pressure. Theresidue was purified by preparative HPLC (using phenylhexyl reversephase column, eluted with gradient of solvent B=0.05% HOAc/CH₃CN andsolvent A=0.05% HOAc/H₂O) to afford(S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(1-methylpyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)ureamono acetate as a colorless solid (29 mg, 25%). ¹H NMR (300 MHz, CDCl₃)δ 9.50 (brs, 1H), 9.00 (brs, 1H), 8.60 (s, 1H), 7.65 (s, 1H), 7.52 (s,1H), 7.30-7.40 (m, 2H), 7.22 (s, 1H), 6.99 (m, 1H), 6.05 (s, 1H), 5.10(s, 1H), 4.01 (s, 3H), 3.37 (m, 1H), 2.96-3.12 (m, 3H), 2.59 (s, 3H),2.50 (m, 1H), 2.25 (m, 1H), 2.10 (s, 3H), 1.30 (s, 9H); LC-MS (ESI) m/z533 (M+H)⁺.

Example 98 Preparation of (R)-tert-butyl3-(4-(3-(3-(5-tert-butylisoxazol-3-yl)ureido)phenoxy)-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylate

Example 98A: Prepared from1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)ureafrom Example 95B (350 mg, 0.780 mmol) and(S)-3-hydroxy-1-tert-butoxycarbonylpyrrolidine (219 mg, 1.17 mmol)according to the procedure described for (S)-tert-butyl3-(4-(3-(3-(5-tert-butylisoxazol-3-yl)ureido)phenoxy)-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylatein Example 96A to afford (R)-tert-butyl3-(4-(3-(3-(5-tert-butylisoxazol-3-yl)ureido)phenoxy)-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylateas a colorless oil (109 mg, 23%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (brs,1H), 9.00 (brs, 1H), 8.57 (s, 1H), 7.50-7.70 (m, 2H), 7.40-7.50 (m, 2H),7.30 (m, 1H), 7.00 (m, 1H), 6.48 (s, 1H), 5.30 (brs, 1H), 4.00 (s, 3H),3.70 (m, 1H), 3.40-3.50 (m, 2H), 3.25 (m, 1H), 2.20-2.40 (m, 2H), 1.40(s, 9H), 1.30 (s, 9H); LC-MS (ESI) m/z 619 (M+H)⁺.

Example 98B: Prepared from (R)-tert-butyl3-(4-(3-(3-(5-tert-butylisoxazol-3-yl)ureido)phenoxy)-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylatefrom the previous step (109 mg, 0.176 mmol) according to the proceduredescribed for(S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)ureadihydrochloride in Example 96B to afford(R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)ureadihydrochloride as a colorless solid (42 mg, 40%). ¹H NMR (300 MHz,CDCl₃) δ 9.30 (brs, 1H), 8.61 (brs, 1H), 7.65 (s, 1H), 7.52 (s, 1H),7.20-7.40 (m, 4H), 6.99 (m, 1H), 6.02 (s, 1H), 5.05 (m, 1H), 4.01 (s,3H), 3.10-3.40 (m, 2H), 3.00 (m, 1H), 2.00-2.40 (m, 4H), 1.40 (s, 9H);LC-MS (ESI) m/z 519 (M+H)⁺.

Example 99 Preparation of(R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(1-methylpyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)ureamono acetate

A solution of(R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)ureadihydrochloride from Example 98B (110 mg, 0.212 mmol) and formaldehyde(0.08 mL of a 37 wt % solution in water, 0.987 mmol) in a mixture of dry1,2-dichloroethane (1.5 mL) and dry N,N-dimethylformamide (0.8 mL) wasstirred at room temperature for 20 mins. Sodium triacetoxyborohydride(135 mg, 0.640 mmol) was added in one portion and stirring continued fora further 45 mins. The reaction mixture was partitioned between aqueous1M sodium hydroxide solution (20 mL) and 10% methanol in dichloromethane(50 mL) and the organic layer was separated and washed with brine (50mL), dried over MgSO₄, and concentrated under reduced pressure. Theresidue was purified by preparative HPLC (Phenomenex phenylhexyl reversephase column, eluted with gradient of solvent B=0.05% HOAc/CH₃CN andsolvent A=0.05% HOAc/H₂O) to afford(R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(1-methylpyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)ureamono acetate as a colorless solid (48 mg, 38%). ¹H NMR (300 MHz, CDCl₃)δ 9.50 (brs, 1H), 9.00 (brs, 1H), 8.60 (s, 1H), 7.65 (s, 1H), 7.52 (s,1H), 7.30-7.40 (m, 2H), 7.22 (s, 1H), 6.99 (m, 1H), 6.05 (s, 1H), 5.11(s, 1H), 4.01 (s, 3H), 3.49 (s, 3H), 3.38 (m, 1H), 2.97-3.06 (m, 3H),2.59 (s, 3H), 2.50 (m, 1H), 2.20 (m, 1H), 1.30 (s, 9H); LC-MS (ESI) m/z533 (M+H)⁺.

Example 100 Preparation of(R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea

Example 100 Step 1: A stirred mixture of1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)ureafrom Example 95B (160 mg, 0.356 mmol), (R)-(−)-epichlorohydrin (65 mg,0.702 mmol), cesium carbonate (120 mg, 0.356 mmol) and potassium iodide(40 mg, 0.241 mmol) in dry N,N-dimethylformamide (4 mL) was heated in asealed vial at 80° C. in a Biotage microwave synthesizer for 90 mins.After cooling to room temperature, the mixture was partitioned betweenwater (50 mL) and a mixture of ethyl acetate (40 mL) and tetrahydrofuran(10 mL). The organic layer was separated, washed with brine (50 mL),dried over MgSO₄ and concentrated under reduced pressure. Purificationvia silica gel chromatography eluting with 100% dichloromethane to 5%methanol in dichloromethane to afford(R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(oxiran-2-ylmethoxy)quinazolin-4-yloxy)phenyl)ureaas a colorless solid (27 mg, 15%). LC-MS (ESI) m/z 506 (M+H)⁺.

Example 100 Step 2: A stirred solution of(R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(oxiran-2-ylmethoxy)quinazolin-4-yloxy)phenyl)ureafrom the previous step (25 mg, 0.0495 mmol) and N-methylpiperazine (10mg, 0.0998 mmol) in dry N,N-dimethylformamide (1 mL) was heated at 70°C. for 15 h. Concentration under reduced pressure gave a residue thatwas triturated with diethyl ether and further purified via silica gelchromatography eluting with 10% methanol in dichloromethane to afford(R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)ureaas a colorless solid (5 mg, 17%). ¹H NMR (300 MHz, CDCl₃) δ 9.40 (brs,1H), 8.62 (s, 1H), 8.30 (brs, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.27-7.39(m, 3H), 7.00 (m, 1H), 5.96 (s, 1H), 4.20-4.28 (m, 3H), 4.02 (s, 3H),2.00-2.80 (m, 14H), 1.29 (s, 9H); LC-MS (ESI) m/z 606 (M+H)⁺.

Example 101 Preparation of1-(3-tert-butylisoxazol-5-yl)-3-(3-(6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-yloxy)phenyl)urea

Example 101A: The intermediate from Example 95B (102 mg, 0.23 mmol) wastreated with cesium carbonate (89 mg, 0.27 mmol) inN,N′-dimethylformamide (4 mL) and stirred at room temperature for 30minutes. tert-Butyl 4-(tosyloxymethyl)piperidine-1-carboxylate (84.3 mg,0.23 mmol) was added and the mixture stirred at 70° C. for 17 h. Aftercooling to room temperature the solid was filtered off and washed withdiethyl ether. The filtrate was concentrated under reduced pressure andthe resulting residue purified by silica gel chromatography(dichloromethane/methanol 9:1) to afford4-((4-(3-(3-(3-tert-butylisoxazol-5-yl)ureido)phenoxy)-6-methoxyquinazolin-7-yloxy)methyl)piperidine-1-carboxylate(71 mg, 48%) as a solid. ¹H NMR (300 MHz, CDCl₃) δ 9.2 (bs, 1H), 8.80(bs, 1H), 8.62 (s, 1H), 7.64 (s, 1H), 7.53 (s, 1H), 7.37-7.27 (m, 3H),6.98 (d, 1H), 6.04 (s, 1H), 4.30-4.05 (m, 2H), 4.05 (s, 5H), 2.79 (t,3H), 2.25-2.05 (m, 1H), 1.99-1.89 (m, 3H), 1.46 (s, 9H), 1.28 (2, 9H);LC-MS (ESI) m/z 647 (M+H)⁺.

Example 101B: To a solution of4-((4-(3-(3-(3-tert-butylisoxazol-5-yl)ureido)phenoxy)-6-methoxyquinazolin-7-yloxy)methyl)piperidine-1-carboxylate(49 mg, 0.062 mmol) in dichloromethane (0.31 mL) was added hydrochloricacid (0.31 mL, 4M in dioxane) and the mixture stirred at roomtemperature for 30 minutes. The solid was filtered off, dissolved inmethanol and concentrated under reduced pressure. The residue was takenin ethyl acetate and a saturated solution of sodium bicarbonate wasadded until the solution became basic. The solid was filtered off,washed thoroughly with water and dried to afford1-(3-tert-butylisoxazol-5-yl)-3-(3-(6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-yloxy)phenyl)ureaas a white solid (23.31 mg, 69%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.10 (bs,1H), 9.65 (bs, 1H), 8.56 (s, 1H), 7.61-7.21 (m, 5H), 6.95 (d, 1H), 6.56(s, 1H), 4.25-3.90 (m, 6H), 3.00 (d, 2H), 2.45 (d, 2H), 2.20-1.79 (m,1H), 1.78-1.51 (m, 4H), 1.25 (s, 9H); LC-MS (ESI) m/z 547 (M+H)⁺.

Example 102 Preparation of1-(3-tert-butylisoxazol-5-yl)-3-(3-(6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-yloxy)phenyl)urea

To a solution of1-(3-tert-butylisoxazol-5-yl)-3-(3-(6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-yloxy)phenyl)urea(82.5 mg, 0.15 mmol) in 1,2-dichloroethane/N,N′-dimethylacetamide (1.3mL, 3:1) was added 37% formaldehyde (24 mL, 0.3 mmol) and acetic acid(10 μL, 0.18 mmol). The mixture was stirred at room temperature for 20minutes. Sodium triacetoxyborohydride (48 mg, 0.23 mmol) was added inportions and the resulting mixture stirred at room temperature for 2 h.Ethyl acetate and 1N sodium hydroxide were added to the mixture, theorganic layer was separated and the water phase extracted three times.The organics were combined, dried (MgSO₄) and concentrated under reducedpressure. The crude material was purified by preparative HPLC(Phenomenex phenylhexyl reverse phase column) to afford1-(3-tert-butylisoxazol-5-yl)-3-(3-(6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-yloxy)phenyl)urea(57 mg, 68%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.75 (bs,1H), 9.21 (bs, 1H), 8.55 (s, 1H), 7.57 (d, 2H), 7.37-7.26 (m, 3H), 6.96(d, 1H), 6.47 (s, 1H), 4.07-3.99 (m, 5H), 2.83-2.79 (m, 2H), 2.17 (s,3H), 1.93-1.76 (m, 5H), 1.39-1.35 (m, 2H), 1.27 (s, 9H); LC-MS (ESI) m/z561 (M+H)⁺.

Example 103 Preparation of(5)-1-(5-tert-butylisoxazol-3-yl)-3-(3-{7-[1-(2,2-difluoroethyl)pyrrolidin-3-yloxy]-6-methoxyquinazolin-4-yloxy}phenyl)urea

Example 103A: To a suspension of1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl]ureafrom Example 95B (0.45 g, 1 mmol), (S)-tert-butyl3-hydroxypyrrolidine-1-carboxylate (0.225 g, 1.2 mmol), and Ph₃P (0.393g, 1.5 mmol) in THF (10 mL) was added di t-butyl azodicarboxylate (0.345g, 1.5 mmol). After it was stirred at room temperature overnight, it wasquenched with saturated NaHCO₃ solution and extracted with CH₂Cl₂.Extracts were dried over MgSO₄ and concentrated under reduced pressure.It was purified by silica gel chromatography with 70-90% EtOAc/hexane aseluants to afford (S)-tert-butyl3-(4-{3-[3-(5-tert-Butylisoxazol-3-yl)ureido]phenoxy}-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylateas solid (0.609 g, 98%). ¹H NMR (300 MHz, CDCl₃) δ 9.4 (s, 1H), 8.8 (s,1H), 8.61 (s, 1H), 7.67 (m, 1H), 7.50 (m, 2H), 7.34 (t, 1H), 7.31 (m,1H), 6.96 (d, 1H), 6.13 (s, 1H), 5.12 (m, 1H), 4.06 (s, 3H), 3.61-3.80(m, 4H), 2.34 (m, 2H), 1.47 (s, 9H), 1.31 (s, 9H); LC-MS (ESI) m/z 619(M+H)⁺.

Example 103B: To a solution of (S)-tert-butyl3-(4-{3-[3-(5-tert-butylisoxazol-3-yl)ureido]phenoxy}-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylate(0.609 g, 0.98 mmol) in CH₂Cl₂ (10 mL) was dropped 4.0 M solution of HClin 1,4-dioxane (2 mL) and it was stirred at room temperature for 4hours. After solvents were concentrated under reduced pressure, it wasdissolved in CH₂Cl₂ with a few milliliters of MeOH and washed withsaturated NaHCO₃ solution. The organic layer was dried over MgSO₄ andconcentrated to dryness under reduced pressure to afford(S)-1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy]phenyl}ureaas a white solid (0.396 g, 77%). ¹H NMR (300 MHz, CDCl₃) δ 9.4 (s, 1H),8.61 (s, 1H), 8.5 (s, 1H), 7.67 (m, 2H), 7.49 (m, 2H), 7.38 (t, 1H),6.99 (d, 1H), 5.99 (s, 1H), 5.05 (m, 1H), 4.01 (s, 3H), 3.40 (m, 1H),3.21 (m, 2H), 3.0 (m, 1H), 2.3 (m, 1H), 2.1 (m, 2H), 1.32 (s, 9H); LC-MS(ESI) m/z 519 (M+H)⁺.

Example 103C: To a solution of(5)-1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy]phenyl}urea(0.198 g, 0.38 mmol) and N,N-diisopropylethylamine (0.5 mL) in CH₂Cl₂(10 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (0.128 g.0.6 mmol) and it was stirred at 40° C. for 1 hour. It was quenched withsaturated NaHCO₃ and extracted with CH₂Cl₂. Extracts were dried overMgSO₄ and concentrated under reduced pressure. It was purified by silicagel chromatography with 70-85% EtOAc/hexane as eluants to afford(S)-1-(5-tert-Butylisoxazol-3-yl)-3-(3-{7-[1-(2,2-difluoroethyl)pyrrolidin-3-yloxy]-6-methoxyquinazolin-4-yloxy}phenyl)ureaas solid (0.098 g, 44%). ¹H NMR (300 MHz, CDCl₃) δ 9.4 (s, 1H), 8.62 (s,1H), 7.81 (s, 1H), 7.65 (t, 1H), 7.54 (s, 1H), 7.40 (t, 1H), 7.33 (m,1H), 7.19 (s, 1H), 7.00 (d, 1H), 5.93 (tt, 1H), 5.87 (s, 1H), 5.05 (m,1H), 4.03 (s, 3H), 3.20 (m, 1H), 3.89-3.09 (m, 4H), 2.8 (m, 1H), 2.5 (m,1H), 2.15 (m, 1H), 1.33 (s, 9H); LC-MS (ESI) m/z 583 (M+H)⁺.

Example 104 Preparation of(S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-{6-methoxy-7-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yloxy]quinazolin-4-yloxy}phenyl)urea

The title compound was prepared as described in Example 103C using(S)-1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy]phenyl}urea(0.198 g, 0.38 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate(0.139 g, 0.6 mmol), and N,N-diisopropylethylamine (0.5 mL) in CH₂Cl₂(10 mL) at 40° C. for 3 hours, which was purified by silica gelchromatography with 70-85% EtOAc/hexane as eluants to afford(5)-1-(5-tert-butylisoxazol-3-yl)-3-(3-{6-methoxy-7-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yloxy]quinazolin-4-yloxy}phenyl)ureaas solid (0.108 g, 47%). ¹H NMR (300 MHz, CDCl₃) δ 9.4 (s, 1H), 8.62 (s,1H), 7.93 (s, 1H), 7.65 (t, 1H), 7.54 (s, 1H), 7.39 (t, 1H), 7.32 (m,1H), 7.20 (s, 1H), 7.01 (d, 1H), 5.89 (s, 1H), 5.06 (m, 1H), 4.03 (s,3H), 3.41 (m, 1H), 3.18 (q, 2H), 2.9-3.08 (m, 3H), 2.44 (m, 1H), 2.2 (m,1H), 1.33 (s, 9H); LC-MS (ESI) m/z 601 (M+H)⁺.

Example 105 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-{7-[1-(2,2-difluoroethyl)piperidin-4-yloxy]-6-methoxyquinazolin-4-yloxy}phenyl)urea

Example 105A: Using the procedure described in Example 103A,1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl]ureafrom Example 95B (0.45 g, 1 mmol) was reacted with tert-butyl4-hydroxypiperidine-1-carboxylate (0.242 g, 1.2 mmol) in the presence ofPh₃P (0.393 g, 1.5 mmol), and di t-butyl azodicarboxylate (0.345 g, 1.5mmol) in THF (10 mL) at room temperature overnight, to afford tert-butyl4-(4-{3-[3-(5-tert-butylisoxazol-3-yl)ureido]phenoxy}-6-methoxyquinazolin-7-yloxy)piperidine-1-carboxylateas a crude product. LC-MS (ESI) m/z 633 (M+H)⁺.

Example 105B: Using the procedure described in Example 103B,tert-butyl4-(4-{3-[3-(5-tert-butylisoxazol-3-yl)ureido]phenoxy}-6-methoxyquinazolin-7-yloxy)piperidine-1-carboxylatewas reacted with 4.0 M HCl/1,4-dioxane at room temperature for 6 hours,to afford1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-yloxy]phenyl}ureaas a crude product. LC-MS (ESI) m/z 533 (M+H)⁺.

Example 105C: The title compound was prepared as described in Example103C, using1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-yloxy]phenyl}urea(0.213 g, 0.4 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (0.128g. 0.6 mmol), and N,N-diisopropylethylamine (0.5 mL) in CH₂Cl₂ (10 mL)at room temperature for 4 hours, which was purified by silica gelchromatography with EtOAc/hexane as eluants to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-{7-[1-(2,2-difluoroethyl)piperidin-4-yloxy]-6-methoxyquinazolin-4-yloxy}phenyl)ureaas a solid (0.011 g, 4%). ¹H NMR (300 MHz, CDCl₃) δ 9.45 (s, 1H), 8.61(s, 1H), 7.66 (t, 1H), 7.55 (s, 1H), 7.31-7.44 (m, 4H), 7.01 (d, 1H),5.90 (tt, 1H), 5.81 (s, 1H), 4.58 (m, 1H), 4.04 (s, 3H), 2.93 (m, 2H),2.80 (td, 2H), 2.53 (m, 2H), 2.15 (m, 2H), 2.00 (m, 2H), 1.33 (s, 9H);LC-MS (ESI) m/z 597 (M+H)⁺.

Example 106 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-{6-methoxy-7-[1-(2,2,2-trifluoroethyl)piperidin-4-yloxy]quinazolin-4-yloxy}phenyl)urea

The title compound was prepared as described in Example 103C, using1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-yloxy]phenyl}urea(0.213 g, 0.4 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate(0.139 g, 0.6 mmol), and N,N-diisopropylethylamine (0.5 mL) in CH₂Cl₂(10 mL) at room temperature for 4 hours, which was purified by silicagel chromatography with EtOAc/hexane as eluants and preparative HPLC(C₁₈ column and 60-90% MeCN/H₂O with 0.05% AcOH) to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-{6-methoxy-7-[1-(2,2,2-trifluoroethyl)piperidin-4-yloxy]quinazolin-4-yloxy}phenyl)ureaas a solid (0.027 g, 11%). ¹H NMR (300 MHz, CDCl₃) δ 9.42 (s, 1H), 8.61(s, 1H), 7.66 (t, 1H), 7.59 (m, 1H), 7.55 (s, 1H), 7.40 (t, 1H), 7.31(m, 2H), 7.02 (d, 1H), 5.83 (s, 1H), 4.60 (m, 1H), 4.04 (s, 3H), 3.04(q, 2H), 3.00 (m, 2H), 2.67 (m, 2H), 2.15 (m, 2H), 2.02 (m, 2H), 1.33(s, 9H); LC-MS (ESI) m/z 615 (M+H)⁺.

Example 107 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)urea

Example 107A Step 1: A suspension of 5,4-dimethoxy-2-nitrobenzoic acid(15.0 g, 0.066 mol) in 20% potassium hydroxide solution (99 mL) washeated at 100° C. for 12 h. The reaction mixture was cooled down to 0°C. and 6N HCl was added to bring the solution to pH 3. The yellow solidwas filtered and the cake washed with cold water. LC/MS: M-1: 212. Thesolid was dissolved in MeOH (400 mL) and HCl gas was bubbled for 2-3min. After stirring at 65° C. for 16 h, the solvent was evaporated undervacuum. The solid was taken up in ethyl acetate and washed with sat'dNaHCO₃ solution. The organic phase was washed with brine and dried overMgSO₄ to yield methyl 5-hydroxy-4-methoxy-2-nitrobenzoate (13.01 g, 87%yield). LC-MS (ESI) m/z 228 (M+H)⁺.

Example 107A Step 2: To solution of methyl5-hydroxy-4-methoxy-2-nitrobenzoate (13.0 g, 0.0572 mol) in DMF (120 mL)and benzyl chloride (7.23 ml, 0.0629 mol), K₂CO₃ (8.69 g, 0.0629 mol)and potassium iodide (0.949 g, 0.0057 mol) were added. The reactionmixture was heated at 90-95° C. overnight. The solvent was evaporatedunder vacuum and the residue was taken in ethyl acetate and washed withwater and brine. After drying over MgSO₄, the solution was concentratedad purified on silica gel column to yield methyl5-(benzyloxy)-4-methoxy-2-nitrobenzoate (13.99 g, 77% yield). ¹HNMR(DMSO-d₆): δ 7.66 (1H, s), 7.40 (6H, m), 5.27 (2H, s), 3.83 (3H, s),3.80 (3H, s). LC-MS (ESI) m/z 318 (M+H)⁺.

Example 107A Step 3: To a solution of methyl5-(benzyloxy)-4-methoxy-2-nitrobenzoate (13.48 g, 0.0425 mol) in MeOH(700 mL) at 55° C., a concentrated solution of Na₂S₂O₄ in water wasadded slowly until no more starting material was observed on TLC. Theheterogeneous solution was concentrated under vacuum. The residue wastreated with water (100 ml) and the mixture extracted with ethyl acetate(2×200 mL). The combined organic layers were washed with water andbrine. After drying over MgSO₄, the solvent was evaporated and theresidue was purified on silica gel column, using ethyl acetate/DCM (1/9)as eluent to yield methyl 2-amino-5-(benzyloxy)-4-methoxybenzoate.Yield: 7.36 g (60%). ¹HNMR (DMSO-d₆): δ 7.34 (5H, m), 7.25 (1H, s), 6.48(2H, s), 6.39 (1H, s), 4.91 (2H, s), 3.80 (3H, s), 3.73 (3H, s). LC-MS(ESI) m/z 288 (M+H)⁺.

Example 107A Step 4: A mixture of methyl2-amino-5-(benzyloxy)-4-methoxybenzoate (7.36 g, 0.025 mol), formamide(25 mL) and acetic acid (6.25 mL) was heated at 130° C. for 24 hr. Afterletting cooling down to room temperature, water was added and theresulting solid was filtered and washed with plenty of cold water. Thesolid was dried under vacuum at 120° C. for 3 hr to yield6-(benzyloxy)-7-methoxyquinazolin-4(3H)-one. Yield: 7.45 g (100%). ¹HNMR(DMSO-d₆): δ 12.15 (1H, s), 8.05 (1H, s), 7.66 (1H, s), 7.44 (5H, m),7.23 (1H, s), 5.28 (2H, s), 3.92 (3H, s). LC-MS (ESI) m/z 207 (M+H)⁺.

Example 107A Step 5: A solution of6-(benzyloxy)-7-methoxyquinazolin-4(3H)-one (7.45 g, 0.026 mol) washeated at 4 hr under argon. The reaction mixture was concentrated todryness, the residue taken in toluene (150 mL) and evaporated to drynessagain. The solid was taken in ethyl acetate and washed with cold sat'dsolution of NaHCO₃. The organic layer was washed with brine and driedover MgSO₄. After solvent evaporation the titled compound was obtained6-(benzyloxy)-4-chloro-7-methoxyquinazoline as a light yellow solid.Yield: 6.34 g (79.8%). ¹HNMR (DMSO-d₆): δ 8.89 (s, 1H), 7.40 (m, 7H),5.34 (s, 2H), 4.00 (s, 3H).

Example 107A Step 6: To a solution of6-(benzyloxy)-4-chloro-7-methoxyquinazoline (3.3 g, 0.01097 mol) and3-aminophenol (1.2 g, 0.01097 mol) in THF (70 mL), Cs₂CO₃ (5.36 g,0.0164 mol) was added at room temperature. The reaction mixture wasstirred at 75° C. for 25 hr. The mixture was filtered and the solid waswashed with ethyl acetate (100 mL). The organic phase was washed withwater, brine and dried over MgSO₄. The solvent was evaporated undervacuum and the solid was triturated with ethyl ether (20 mL). The solidwas filtered and washed with ethyl ether to afford3-(6-(benzyloxy)-7-methoxyquinazolin-4-yloxy)aniline (3.72 g, 90%yield). ¹HNMR (DMSO-d₆): δ 8.55 (s, 1H), 7.66 (s, 1H), 7.46 (m, 8H),7.08 (t, 1H), 6.49 (d, 1H), 6.40 (m, 2H), 5.30 (s, 2H), 4.02 (s, 3H).LC-MS (ESI) m/z 508 (M+H)⁺.

Example 107A Step 7: A mixture of3-(6-(benzyloxy)-7-methoxyquinazolin-4-yloxy)aniline (3.64 g, 0.00974mol) and Pd/C (10%) in ethanol/THF (400 mL, 3/1) was hydrogenated at 1atm. of H₂, at 50-55° C. for 3 h. The mixture was filtered throughCelite and the filtrate was concentrated to about 100 mL. The crude wasleft in the fridge overnight. The solid was filtered and washed withsmall portion of cold ethanol to afford4-(3-aminophenoxy)-7-methoxyquinazolin-6-ol (2.05 g, 74.3% yield). ¹HNMR(DMSO-d₆): δ 10.30 (1H, s), 8.49 (1H, s), 7.46 (1H, s), 7.34 (1H, s),7.07 (1H, m), 6.48 (1H, m), 6.40 (2H, m), 5.29 (2H, s), 3.90 (3H, s).LC-MS (ESI) m/z 284 (M+H)⁺.

Example 107B: To a solution of4-(3-aminophenoxy)-7-methoxyquinazolin-6-ol (2.0 g, ˜0.0070 mol) in DMF(10 mL), phenyl 5-tert-butylisoxazol-3-ylcarbamate (1.74 g, 0.0067 mol)was added. The reaction mixture was stirred at 60° C., overnight. Thesolvent was evaporated under vacuum and the residue was sonicated in thepresence of ethyl ether (60 mL). The solid was filtered and washed withethyl ether to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)urea(2.75 g, 87.5% yield). ¹HNMR (DMSO-d₆): δ 10.53 (s, 1H), 9.57 (s, 1H),8.99 (s, 1H), 8.50 (s, 1H), 7.52 (d, 2H), 7.37 (m, 2H), 7.25 (d, 1H),6.95 (d, 1H), 6.18 (s, 1H), 4.00 (s, 3H), 1.30 (s, 9H); LC-MS (ESI) m/z450 (M+H)⁺.

Example 108 Preparation of (S)-tert-butyl3-(4-(3-(3-(5-tert-butylisoxazole-3-yl)ureido)phenoxy)-7-methoxyquinazolin-6-yloxy)pyrrolidine-1-carboxylate

To a stirred solution of diisopropylazodicarboxylate (155 μL, 0.80 mmol)in THF (5 mL) under argon, triphenylphosphine (209 mg, 0.80 mmol) wasadded. After stirring 15 at room temperature, a solution of(R)-tert-butyl pyrrolidinol carboxylate (150 mg, 0.80 mmol)1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)urea(300 mg, 0.668 mmol) in THF (3 mL) was added. Reaction mixture was leftstirring at room temperature overnight. The solvent was evaporated andthe residue was purified on silica gel column, using ethylacetate/hexane as eluent. The titled compound was obtained as a foam.Yield: 330 mg (80%). ¹HNMR (dmso-d6): δ 9.58 (1H, s), 9.00 (1H, s), 8.57(1H, s), 7.60 (2H, m), 7.40 (2H, m), 7.26 (1H, m), 6.98 (1H, m), 6.48(1H, s), 5.30 (1H, m), 3.99 (3H, s), 3.50 (4H, m), 2.20 (2H, m), 1.27(9H, s), 1.02 (H, s). LC-MS (ESI) m/z 619 (M+H)⁺.

Example 109 Preparation of(S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(1-methylpyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)urea

Example 109A: To a solution of (S)-tert-butyl3-(4-(3-(3-(5-tert-butylisoxazole-3-yl)ureido)phenoxy)-7-methoxyquinazolin-6-yloxy)pyrrolidine-1-carboxylate(300 mg, ˜0.40 mmol), a 4N solution of HCl in dioxane (1 ml, 4 mmol) wasadded. The reaction mixture was stirred at room temperature overnight.The resulting solid was filtered and washed with plenty of ethyl etherto yield(S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(pyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)ureadihydrochloride (215 mg, 91%). LC-MS (ESI) m/z 519 (M+H)⁺.

Example 109B: To a solution of(S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(pyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)ureadihydrochloride (110 mg, 0.18 mmol) and acetic acid (12 μL, 0.2 mmol) inDMA (1.5 mL), a 37% aqueous solution of formaldehyde (29 μL, 0.36 mmol)and NaBH(OAc)₃ (57 mg, 0.27 mmol) were added at room temperature. After2 h, the reaction mixture was diluted with water and extracted with amixture 8/2 of ethyl acetate/THF. After drying over MgSO₄, the solutionwas evaporated and concentrated to dryness. The crude product waspurified on HPLC. Yield: 82 mg (85%). ¹HNMR (dmso-d6): δ 10.62 (1H, s),10.10 (1H, s), 8.55 (1H, s), 7.59 (1H, s), 7.45 (1H, s), 7.37 (3H, m),6.93 (1H, d), 6.47 (1H, s), 5.12 (1H, m), 3.99 (3H, s), 2.76 (4H, m),2.35 (2H, m), 2.28 (3H, s), 1.25 (9H, s). LC-MS (ESI) m/z 533 (M+H)⁺.

Example 110 Preparation of(S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(1-(2,2-difluoroethyl)pyrrolidin-3-yloxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea

To a mixture of a solution of NaHCO₃ (47 mg in 1.5 mL, 0.561 mmol) andethyl acetate (3 mL), 2,2-difluoroethyl trifluoromethanesulfonate (48μL, 0.22 mmol) was added. After heating at 40 C,(S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(pyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)ureadihydrochloride (110 mg, 0.187 mmol) was added. The reaction mixture wasstirred at 40° C. for 1 h. The mixture was diluted with ethyl acetateand organic layer was washed with brine. After drying over MgSO₄, thesolvent was evaporated and the crude product purified on silica gel,using dichloromethane/methanol as mobile phase. Yield: 40 mg (37%).¹HNMR (dmso-d6): δ 9.58 (1H, s), 9.00 (1H, s), 8.56 (1H, s), 7.59 (1H,s), 7.47 (1H, s), 7.40 (2H, m), 7.25 (1H, d), 6.97 (1H, d), 6.48 (1H,s), 5.15 (1H, m), 5.15 (1H, m), 3.99 (3H, s), 2.91 (6H, m), 2.40 (1H,m), 1.90 (1H, m), 1.27 (9H, s). LC-MS (ESI) m/z 583 (M+H)⁺.

Example 111 Preparation of(S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea-

Example 111A: Synthesis of(S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(oxiran-2-ylmethoxy)quinazolin-4-yloxy)phenyl)urea

To a solution of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)urea(120 mg, 0.267 mmol) in DMF (4 mL), Cs₂CO₃ (0.32 mmol) and (S) (+)epichlorohydrin (104 μL, 1.33 mmol) was added. The reaction mixture wasreacted at 80 C under microwave condition for 2 h. The mixture wasdiluted with a ethyl acetate/THF (15/5) mixture and washed with water,brine and dried over MgSO₄. After removal of the solvent, the titledcompound was obtained as an off-white solid. Yield: 135 mg (100%). LC-MS(ESI) m/z 506 (M+H)⁺.

Example 111B: To a solution of(S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(oxiran-2-ylmethoxy)quinazolin-4-yloxy)phenyl)urea(129 mg, 0.260 mmol) in DMF (2 mL), 1-methylpiperazine (144 μL, 1.30mmol) added. The reaction mixture was stirred at 70 C for 8 h. Themixture was purified on HPLC. Yield: 28 mg (17%). ¹HNMR (dmso-d6): δ9.74 (1H, s), 9.18 (1H, s), 8.55 (1H, s), 7.58 (2H, s), 7.41 (2H, m),7.26 (1H, d), 6.97 (1H, d), 6.48 (1H, s), 4.90 (1H, bs), 4.15 (2H, m),4.00 (3H, s), 2.40 (10H, m), 2.06 (3H, s), 1.29 (9H, s). LC-MS (ESI) m/z606 (M+H)⁺.

Example 112 Preparation of(R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea

Example 112A:1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)urea(320 mg, 0.712 mol) and (R)(−)epichlorohydrin (288 μL, 3.56 mmol) werereacted using the same procedure as described before from Example 111Ato afford(R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(oxiran-2-ylmethoxy)quinazolin-4-yloxy)phenyl)urea(160 mg, 44%). LC-MS (ESI) m/z 506 (M+H)⁺.

Example 112B: Starting from(R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(oxiran-2-ylmethoxy)quinazolin-4-yloxy)phenyl)urea,followed the same procedure as described in Example 111B to yield(R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea(18 mg, 12%). ¹HNMR (dmso-d6): δ 9.74 (1H, s), 9.18 (1H, s), 8.55 (1H,s), 7.58 (2H, s), 7.41 (2H, m), 7.26 (1H, d), 6.97 (1H, d), 6.48 (1H,s), 4.90 (1H, bs), 4.15 (2H, m), 4.00 (3H, s), 2.40 (10H, m), 2.06 (3H,s), 1.29 (9H, s). LC/MS: M+1: 606.

Example 113 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-phenylisoxazol-3-yl)urea

Example 113A: To a slurry of cesium carbonate (13.3 mmol) in THF wasadded 3-aminophenol (1.45 g, 13.3 mmol). After stirring 15 minutes atroom temperature, 4-chloro-6,7-dimethoxyquinazoline (3.0 g, 13.3 mmol)was added and the reaction mixture heated at 50° C. overnight. Themixture was diluted with EtOAc and washed with water and brine, driedover MgSO₄, filtered, and concentrated in vacuo. to give3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (3.62 g, 12.2 mmol, 91%). ¹HNMR (300 MHz, DMSO-d₆) δ 8.55 (s, 1H), 7.51 (s, 1H), 7.37 (s, 1H), 7.09(t, 1H), 6.50 (d, 1H), 6.43 (s, 1H), 6.38 (d, 1H), 5.30 (br s, 2H), 3.99(s, 3H), 3.97 (s, 3H); LC-MS (ESI) m/z 298 (M+H)⁺.

Example 113B: 5-Phenylisoxazol-3-amine (428 mg, 2.67 mmol) intetrahydrofuran (4.8 mL) was treated with potassium carbonate (481 mg,3.47 mmol) and phenyl choloroformate (0.67 mL, 5.3 mmol). The reactionmixture was stirred at room temperature overnight. The mixture wasfiltered through a celite pad, washed with ethyl acetate andconcentrated to dryness. The residue was taken into chloroform, washedwith brine, and the organics dried (MgSO₄) and concentrated. The residuewas purified by silica gel chromatography (hexane/ethyl acetate 8:2) togive phenyl 5-phenylisoxazol-3-ylcarbamate (599 mg, 80%) as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 7.92 (bs, 1H), 7.78 (d, 2H), 7.45 (m,6H), 7.26 (m, 2H), 7.12 (s, 1H); LC-MS (ESI) m/z 281 (M+H)⁺.

Example 113C: 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example113A (90 mg, 0.3 mmol), in tetrahydrofuran (1.5 mL) was treated withN,N-diisopropylethylamine (78 μl, 0.45 mmol), 4-(dimethylamino)pyridine(1.8 mg, 0.015 mmol) and phenyl 5-phenylisoxazol-3-ylcarbamate from theprevious step (126 mg, 0.45 mmol). The reaction mixture was heated to50° C. for 2.5 h. After cooling to room temperature, the mixture waspartitioned between dichloromethane and a saturated solution of sodiumbicarbonate. The water phase was back extracted three times withdichloromethane and the organics combined and dried (MgSO₄).Concentration under reduced pressure gave a residue which was purifiedby preparative HPLC (phenylhexyl reverse phase column). The obtainedsolid was triturated with anhydrous diethyl ether to afford1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-phenylisoxazol-3-yl)ureaas a white solid (47.16 mg, 32%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.75 (s,1H), 9.08 (s, 1H), 8.58 (s, 1H), 7.86 (d, 2H), 7.87-7.51 (m, 4H),7.51-7.40 (m, 2H), 7.31-7.21 (m, 3H), 7.00 (d, 1H), 4.00 (s, 6H); LC-MS(ESI) m/z 484 (M+H)⁺.

Example 114 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-phenylisoxazol-5-yl)urea

Example 114A: 3-Phenylisoxazol-5-amine (456 mg, 2.85 mmol) was preparedaccording to the procedure described in Example 113B by using an excessof phenyl chloroformate (10.2 mmol). Purification by silica gelchromatography (hexane/ethyl acetate 8:2) gave phenyl3-phenylisoxazol-5-ylcarbamate (675 mg, 84%) as a white solid. ¹H NMR(300 MHz, CDCl₃) δ 7.80 (d, 2H), 7.47-7.40 (m, 5H), 7.32-7.19 (m, 3H),6.54 (s, 1H); LC-MS (ESI) m/z 281 (M+H)⁺.

Example 114B: The title compound was prepared according to the proceduredescribed in Example 113C, by using compound3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (90 mg, 0.3mmol) and compound phenyl 3-phenylisoxazol-5-ylcarbamate from theprevious step (126 mg, 0.45 mmol) to afford1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-phenylisoxazol-5-yl)ureaas a white solid (63.34 mg, 44%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.4 (s,1H), 9.14 (s, 1H), 8.5 (s, 1H), 7.83 (d, 2H), 7.83-7.48 (m, 7H), 7.42(d, 1H), 7.00 (d, 1H), 6.56 (s, 1H), 4.00 (s, 6H); LC-MS (ESI) m/z 484(M+H)⁺.

Example 115 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-methoxy-5-(trifluoromethyl)phenyl)urea

Example 115A Step 1: 1-Methoxy-3-nitro-5-(trifluoromethyl)benzene (1.33g, 6.0 mmol) was reacted according to the procedure in Example 16A Step3 to give 3-methoxy-5-(trifluoromethyl)aniline (1.11 g, 5.8 mmol, 97%).LC-MS (ESI) m/z 192 (M+H)⁺.

Example 115A Step 2: To THF was added3-methoxy-5-(trifluoromethyl)aniline (1.10 g, 5.7 mmol), potassiumcarbonate (2 equivalents), phenyl chloroformate (3 equivalents) and4-dimethylaminopyridine (0.1 equivalent) and the reaction was stirred atroom temperature overnight. The mixture was diluted with EtOAc,filtered, concentrated in vacuo, and purified by silica gel columnchromatography (5-15% EtOAc/hexanes) to give phenyl3-methoxy-5-(trifluoromethyl)phenylcarbamate (1.02 g, 3.28 mmol, 57%).¹H NMR (300 MHz, DMSO-d₆) δ 10.59 (s, 1H), 7.50-7.35 (m, 4H), 7.31-7.22(m, 3H), 6.94 (s, 1H), 3.81 (s, 3H); LC-MS (ESI) m/z 312 (M+H)⁺.

Example 115B: 3-Aminothiophenol (1.42 mL, 13.3 mmol) and4-chloro-6,7-dimethoxyquinazoline (3.0 g, 13.3 mmol) were reacted usingthe procedure described in Example 46 to give3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (4.32 g, 13.8 mmol, 100%(wet with H₂O)). ¹H NMR (300 MHz, DMSO-d₆) δ 8.70 (s, 1H), 7.33 (s, 1H),7.31 (s, 1H), 7.13 (t, 1H), 6.80 (s, 1H), 6.73 (d, 1H), 6.68 (d, 1H),5.34 (br s, 2H), 3.98 (s, 3H), 3.97 (s, 3H); LC-MS (ESI) m/z 314 (M+H)⁺.

Example 115C: To 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from theprevious step (94 mg, 0.3 mmol) in THF (3 mL) was added phenyl3-methoxy-5-(trifluoromethyl)phenylcarbamate from Example 115A (140 mg,0.45 mmol), diisopropylethylamine (80 uL, 0.45 mmol), and4-dimethylaminopyridine (4 mg, 0.03 mmol). The solution was stirred at50° C. overnight, allowed to cool to room temperature, and diluted withEtOAc. The solid was then filtered to give1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-methoxy-5-(trifluoromethyl)phenyl)urea(89 mg, 0.17 mmol, 56%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.12 (s, 1H), 9.02(s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.55 (d, 1H), 7.48 (s, 1H), 7.44(t, 1H), 7.35 (s, 1H), 7.34 (s, 1H), 7.29-7.24 (m, 2H), 6.85 (s, 1H),3.99 (s, 6H), 3.81 (s, 3H); LC-MS (ESI) m/z 531 (M+H)⁺.

Example 116 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-methoxy-5-(trifluoromethyl)phenyl)urea

3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 g, 0.3mmol) and phenyl 3-methoxy-5-(trifluoromethyl)phenylcarbamate fromExample 115A (140 mg, 0.45 mmol) were reacted using the procedure inExample 115C to give1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-methoxy-5-(trifluoromethyl)phenyl)urea(71 mg, 0.14 mmol, 46%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.19 (s, 1H), 9.08(s, 1H), 8.56 (s, 1H), 7.62-7.55 (m, 2H), 7.48 (s, 1H), 7.45-7.37 (m,2H), 7.31-7.24 (m, 2H), 6.95 (d, 1H), 6.84 (s, 1H), 4.00 (s, 3H), 3.99(s, 3H), 3.80 (s, 3H); LC-MS (ESI) m/z 515 (M+H)⁺.

Example 117 Preparation of1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)urea

Example 117A Step 1: To 1-methoxy-3-nitro-5-(trifluoromethyl)benzene(2.21 g, 10.0 mmol) in DCM at 0° C. was added BBr₃ (10 equivalents)dropwise over 5 minutes. The solution was allowed to warm to r.tovernight at which point it was quenched with sat. aqueous NaHCO₃ andextracted with EtOAc. The organic layer was washed with H₂O and brine,dried over MgSO₄, filtered, and concentrated in vacuo to give3-nitro-5-(trifluoromethyl)phenol (778 mg, 3.76 mmol, 37%), ¹H NMR (300MHz, DMSO-d₆) δ 11.22 (s, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 7.51 (s, 1H);LC-MS (ESI) m/z 208 (M+H)⁺.

Example 117A Step 2: 3-nitro-5-(trifluoromethyl)phenol (770 mg, 3.72mmol) and 1-bromo-2-methoxyethane (1.75 mL, 19 mmol) were reacted usingthe procedure described in Example 40A Step 3 to give1-(2-methoxyethoxy)-3-nitro-5-(trifluoromethyl)benzene (456 mg, 1.72mmol, 46%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (s, 1H), 8.02 (s, 1H), 7.80(s, 1H), 4.36 (dd, 2H), 3.71 (dd, 2H), 3.31 (s, 3H); LC-MS (ESI) m/z 266(M+H)⁺.

Example 117A Step 3: The procedure described in Example 16A Step 3 wasused, but substituting the benzoate with1-(2-methoxyethoxy)-3-nitro-5-(trifluoromethyl)benzene (450 mg, 1.70mmol) to give 3-(2-methoxyethoxy)-5-(trifluoromethyl)aniline (419 mg,1.76 mmol, 100%), ¹H NMR (300 MHz, DMSO-d₆) δ 6.49 (s, 1H), 6.39 (s,1H), 6.36 (s, 1H), 5.73 (br s, 2H), 4.05 (dd, 2H), 3.63 (dd, 2H), 3.29(s, 3H); LC-MS (ESI) m/z 236 (M+H)⁺.

Example 117A Step 4: 3-(2-methoxyethoxy)-5-(trifluoromethyl)aniline (415mg, 1.75 mmol) was reacted as described in Example 115A Step 2 to givephenyl 3-(2-methoxyethoxy)-5-(trifluoromethyl)phenylcarbamate (524 mg,1.48 mmol, 84%). LC-MS (ESI) m/z 356 (M+H)⁺.

Example 117B: Using the procedure described in Example 46, 3-aminophenol(1.21 g, 11.1 mmol) and4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (2.85 g, 10.6 mmol)were reacted to give3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline (1.22 g, 3.58mmol, 34%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.54 (s, 1H), 7.52 (s, 1H), 7.39(s, 1H), 7.09 (t, 1H), 6.50 (d, 1H), 6.53 (s, 1H), 6.40 (d, 1H), 5.30(br s, 2H), 4.33 (t, 2H), 3.97 (s, 3H), 3.77 (t, 2H), 3.31 (s, 3H);LC-MS (ESI) m/z 342 (M+H)⁺.

Example 117C: 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)anilinefrom the previous step (102 mg, 0.3 mmol) was reacted with phenyl3-(2-methoxyethoxy)-5-(trifluoromethyl)phenylcarbamate from Example 117A(160 mg, 0.45 mmol) in the manner described in Example 115C. The finalproduct was purified by column chromatography (25-100% EtOAc/hexanesthen 5-10% MeOH/DCM) to give1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)urea(137 mg, 0.23 mmol, 76%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.10 (s, 1H), 9.04(s, 1H), 8.56 (s, 1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.49 (s, 1H),7.45-7.38 (m, 2H), 7.32-7.26 (m, 2H), 6.96 (d, 1H), 6.87 (s, 1H),4.37-4.31 (m, 2H), 4.19-4.12 (m, 2H), 4.00 (s, 3H), 3.80-3.73 (m, 2H),3.70-3.63 (m, 2H), 3.36 (s, 3H), 3.31 (s, 3H); LC-MS (ESI) m/z 603(M+H)⁺.

Example 118 Preparation of1-(3-tert-butylphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 118A: To THF (15 mL) was added 3-tert-butylaniline (447 mg, 3mmol), potassium carbonate (828 mg, 6 mmol), phenyl chloroformate (1.13mL, 9 mmol), and dimethylaminopyridine (36 mg, 0.30 mmol) and thereaction stirred at room temperature overnight. The mixture was dilutedwith EtOAc, filtered, concentrated in vacuo, and purified by silica gelcolumn chromatography (5-15% EtOAc/hexanes) to give phenyl3-tert-butylphenylcarbamate (458 mg, 1.70 mmol, 57%). ¹H NMR (300 MHz,DMSO-d₆) δ 10.14 (s, 1H), 7.59 (s, 1H), 7.49-7.10 (m, 7H), 7.08 (d, 1H),1.25 (s, 9H); LC-MS (ESI) m/z 270 (M+H)⁺.

Example 118B: The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (90 mg, 0.3mmol) and phenyl 3-tert-butylphenylcarbamate from the previous step (114mg, 0.42 mmol) using Example 115C. The final product was purified bysilica gel column chromatography (25-100% EtOAc/hexanes) to give1-(3-tert-butylphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(83 mg, 0.18 mmol, 58%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.70(s, 1H), 8.57 (s, 1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.50-7.36 (m, 3H),7.31-7.14 (m, 3H), 7.05-6.86 (m, 2H), 4.00 (s, 6H), 1.28 (s, 9H); LC-MS(ESI) m/z 473 (M+H)⁺.

Example 119 Preparation of1-(3-tert-butylphenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

The title compound was prepared from3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (103 mg, 0.3 mmol) and phenyl 3-tert-butylphenylcarbamate fromExample 118A (114 mg, 0.42 mmol) using Example 115C. The final productwas purified by silica gel column chromatography (25-100% EtOAc/hexanes)to give1-(3-tert-butylphenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea(74 mg, 0.14 mmol, 48%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.70(s, 1H), 8.56 (s, 1H), 7.61-7.58 (m, 2H), 7.49-7.36 (m, 3H), 7.27-7.16(m, 3H), 7.03 (d, 1H), 6.92 (d, 1H), 4.38-4.32 (m, 2H), 4.00 (s, 3H),3.81-3.73 (m, 2H), 3.33 (s, 3H), 1.26 (s, 9H); LC-MS (ESI) m/z 517(M+H)⁺.

Example 120 Preparation of1-(3-tert-butylphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg,0.3 mmol) and phenyl 3-tert-butylphenylcarbamate from Example 118A (114mg, 0.42 mmol) were reacted as described in Example 115C to give1-(3-tert-butylphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(71 mg, 0.14 mmol, 48%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.84 (s, 1H), 8.70(s, 2H), 7.84 (s, 1H), 7.53-7.39 (m, 3H), 7.35 (s, 2H), 7.28-7.17 (m,3H), 7.02 (d, 1H), 3.99 (s, 6H), 1.27 (s, 9H); LC-MS (ESI) m/z 489(M+H)⁺.

Example 121 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-methylisoxazol-3-yl)urea

Example 121A: 5-methylisoxazol-3-amine (490 mg, 5.0 mmol) was reacted asdescribed in Example 118A to give phenyl 5-methylisoxazol-3-ylcarbamate(425 mg, 1.95 mmol, 39%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.14 (s, 1H),7.45 (t, 2H), 7.29 (d, 1H), 7.21 (d, 2H), 6.47 (s, 1H), 2.38 (s, 3H);LC-MS (ESI) m/z 219 (M+H)⁺.

Example 121B: 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example113A (89 mg, 0.3 mmol) and phenyl 5-methylisoxazol-3-ylcarbamate fromthe previous step (98 mg, 0.42 mmol) were reacted using Example 115C togive1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-methylisoxazol-3-yl)urea(31 mg, 0.074 mmol, 25%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.53 (s, 1H), 9.01(s, 1H), 8.56 (s, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 7.45-7.35 (m, 2H),7.26 (d, 1H), 6.97 (d, 1H), 6.51 (s, 1H), 3.99 (s, 6H), 2.35 (s, 3H);LC-MS (ESI) m/z 422 (M+H)⁺.

Example 122 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea

Example 122A Step 1: A stirred suspension of sodium hydride (1.95 g, 60%dispersion in mineral oil, 48.75 mmol) in dry tetrahydrofuran (25 mL),was heated to 75° C. To this was added a mixture of methyl isobutyrate(3.19 g, 31.25 mmol) and dry acetonitrile (2.56 mL, 48.75 mmol),dropwise over the course of 45 mins. The resulting pale yellowsuspension was heated at 70° C. for a further 15 h. After cooling toroom temperature, the reaction mixture was poured into water (150 mL)and the resulting solution was extracted with diethyl ether (2×100 mL).The aqueous layer was separated, acidified to pH 2 with aqueous 2Nhydrochloric acid and extracted with diethyl ether (2×100 mL). Thecombined ether layers were dried over MgSO₄ then concentrated underreduced pressure to afford 4-methyl-3-oxopentanenitrile as a yellow oil(2.71 g, 78%) which was used in the next step without furtherpurification. ¹H NMR (300 MHz, CDCl₃) δ 3.53 (s, 2H), 2.81 (septet, J=6Hz, 1H), 1.21 (d, J=6 Hz, 6H).

Example 122A Step 2: To a stirred solution of sodium hydroxide (238 mg,5.95 mmol) and 4-methyl-3-oxopentanenitrile from the previous step (600mg, 5.41 mmol) in a mixture of water (5 mL) and ethanol (5 mL), wasadded hydroxylamine sulfate (977 mg, 5.95 mmol). The reaction mixturewas adjusted to pH 7.5 with aqueous 1N sodium hydroxide solution, thenheated to 80° C. for 15 h. After cooling to room temperature the solventwas removed under reduced pressure. The resulting solid was partitionedbetween water (50 mL) and dichloromethane (50 mL). The organic layer wasseparated, washed with brine (50 mL), dried over MgSO₄, thenconcentrated under reduced pressure to afford3-isopropylisoxazol-5-amine as a cream solid (530 mg, 78%) which wasused in the next step without further purification. ¹H NMR (300 MHz,CDCl₃) δ 5.00 (s, 1H), 4.39 (brs, 2H), 2.89 (septet, J=6 Hz, 1H), 1.23(d, J=6 Hz, 6H); LC-MS (ESI) m/z 127 (M+H)⁺.

Example 122A Step 3: To a stirred mixture of3-isopropylisoxazole-5-amine (250 mg, 1.98 mmol) and potassium carbonate(634 mg, 4.59 mmol) in dry tetrahydrofuran (6 mL) was added phenylchloroformate (341 mg, 2.18 mmol). The reaction mixture was stirred atroom temperature for 3.5 h, then additional phenyl chloroformate (341mg, 2.18 mmol) was added and stirring was continued for a further 15 h.The resulting mixture was partitioned between water (50 mL) anddichloromethane (50 mL). The organic layer was separated, washed withbrine (50 mL), dried over MgSO₄, then concentrated under reducedpressure to give a yellow oil. Purification via silica gelchromatography eluting with 4% to 40% ethyl acetate in hexanes affordedphenyl 3-isopropylisoxazol-5-ylcarbamate as a colorless solid (330 mg,68%). ¹H NMR (300 MHz, CDCl₃) δ 7.76 (brs, 1H), 7.40-7.45 (m, 2H),7.18-7.31 (m, 3H), 6.07 (s, 1H), 3.02 (septet, J=6 Hz, 1H), 1.28 (d, J=6Hz, 6H); LC-MS (ESI) m/z 247 (M+H)⁺.

Example 122B: A stirred solution of3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg,0.30 mmol), phenyl 3-isopropylisoxazol-5-ylcarbamate from the previousstep (89 mg, 0.36 mmol), N,N-diisopropylethylamine (58 mg, 0.45 mmol)and 4-(dimethylamino)pyridine (1.8 mg, 0.015 mmol) in drytetrahydrofuran (1.5 mL), was heated at 50° C. for 30 mins. Aftercooling to room temperature, concentration under reduced pressure gave aresidue which was partitioned between water (50 mL) and dichloromethane(50 mL). The organic layer was separated, washed with brine (50 mL),dried over MgSO₄ and concentrated under reduced pressure. The residuewas purified by preparative HPLC (using phenylhexyl reverse phasecolumn, eluted with gradient of solvent B=0.05% HOAC/CH₃CN and solventA=0.05% HOAc/H₂O) to afford1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)ureaas a colorless solid (25 mg, 19%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.30(brs, 1H), 9.14 (s, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.39-7.44 (m, 2H),7.31 (m, 1H), 6.99 (m, 1H), 5.99 (s, 1H), 4.00 (s, 6H), 2.90 (septet,J=6 Hz, 1H), 1.19 (d, J=6 Hz, 6H); LC-MS (ESI) m/z 450 (M+H)⁺.

Example 123 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-yl)urea

Example 123A Step 1: Prepared from methyl tetrahydropyran-4-carboxylate(3 g, 20.80 mmol) according to the method described for4-methyl-3-oxopentanenitrile in Example 122A Step 1, to afford3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile as a yellow oil (760mg, 24%) which was used in the next step without further purification.¹H NMR (300 MHz, CDCl₃) δ 3.96-4.05 (m, 2H), 3.52 (s, 1H), 3.42-3.50 (m,2H), 2.82 and 2.59 (2×m, 1H), 1.67-1.90 (m, 4H).

Example 123A Step 2: Prepared from3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile (350 mg, 2.29 mmol)according to the method described for 3-isopropylisoxazol-5-amine inExample 122A Step 2, to afford3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-amine as a colorless solid (170mg, 44%) which was used in the next step without further purification.¹H NMR (300 MHz, CDCl₃) δ 5.01 (s, 1H), 4.40 (brs, 2H), 4.02-4.05 (m,2H), 3.46-3.55 (m, 2H), 2.87 (m, 1H), 1.71-1.84 (m, 4H); LC-MS (ESI) m/z169 (M+H)⁺.

Example 123A Step 3: Prepared from3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-amine (170 mg, 1.01 mmol)according to the method described for phenyl3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to affordphenyl 3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-ylcarbamate as a colorlesssolid (164 mg, 56%). ¹H NMR (300 MHz, CDCl₃) δ 7.93 (brs, 1H), 7.39-7.45(m, 2H), 7.18-7.32 (m, 3H), 6.09 (s, 1H), 4.02-4.08 (m, 2H), 3.48-3.57(m, 2H), 2.96 (m, 1H), 1.78-1.89 (m, 4H); LC-MS (ESI) m/z 289 (M+H)⁺.

Example 123B: 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example113A (89 mg, 0.3 mmol) was reacted with phenyl3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-ylcarbamate (104 mg, 0.36 mmol)according to the method described for1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)ureain Example 122B to afford1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-yl)ureaas a cream solid (68 mg, 46%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.25 (brs,1H), 9.07 (s, 1H), 8.56 (s, 1H), 7.56-7.58 (m, 2H), 7.39-7.44 (m, 2H),7.31 (m, 1H), 6.99 (m, 1H), 6.01 (s, 1H), 3.99-4.00 (2×s, 6H), 3.86-3.90(m, 2H), 3.40-3.46 (m, 2H), 2.90 (m, 1H), 1.69-1.76 (m, 2H), 1.60-1.69(m, 2H); LC-MS (ESI) m/z 492 (M+H)⁺.

Example 124 Preparation of1-(3-cyclopropylisoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 124A Step 1: Prepared from methyl cyclopropane carboxylate (3.13g, 31.25 mmol) according to the method described for4-methyl-3-oxopentanenitrile Example 122A Step 1, to afford3-cyclopropyl-3-oxopentanenitrile as a yellow oil (2.12 g, 62%) whichwas used in the next step without further purification. ¹H NMR (300 MHz,CDCl₃) δ 3.63 (s, 2H), 2.12 (m, 1H), 1.18-1.25 (m, 2H), 1.10-1.16 (m,2H).

Example 124A Step 2: Prepared from 3-cyclopropyl-3-oxopentanenitrile (1g, 9.17 mmol) according to the method described for3-isopropylisoxazol-5-amine in Example 122A Step 2, to afford3-cyclopropylisoxazol-5-amine as a yellow oil (760 mg, 67%) which wasused in the next step without further purification. ¹H NMR (300 MHz,CDCl₃) δ 4.78 (s, 1H), 4.37 (brs, 2H), 1.85 (m, 1H), 0.93-0.99 (m, 2H),0.75-0.81 (m, 2H); LC-MS (ESI) m/z 125 (M+H)⁺.

Example 124A Step 3: Prepared from 3-cyclopropylisoxazol-5-amine (300mg, 2.42 mmol) according to the method described for phenyl3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to affordphenyl 3-cyclopropylisoxazol-5-ylcarbamate as a yellow oil (420 mg,71%). ¹H NMR (300 MHz, CDCl₃) δ 7.99 (brs, 1H), 7.39-7.44 (m, 2H), 7.29(m, 1H), 7.15-7.20 (m, 2H), 5.84 (s, 1H), 1.98 (m, 1H), 1.01-1.05 (m,2H), 0.82-0.88 (m, 2H); LC-MS (ESI) m/z 245 (M+H)⁺.

Example 124B: 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example113A (89 mg, 0.3 mmol) and phenyl 3-cyclopropylisoxazol-5-ylcarbamatefrom the previous step (88 mg, 0.36 mmol) were reacted according to themethod described for1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)ureain Example 122B to afford1-(3-cyclopropylisoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)ureaas a colorless solid (65 mg, 49%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.17(brs, 1H), 9.05 (brs, 1H), 8.56 (s, 1H), 7.56 (s, 2H), 7.38-7.44 (m,2H), 7.29 (m, 1H), 6.99 (m, 1H), 5.77 (s, 1H), 3.98-4.00 (2×s, 6H), 1.91(m, 1H), 0.94-0.99 (m, 2H), 0.71-0.75 (m, 2H); LC-MS (ESI) m/z 448(M+H)⁺.

Example 125 Preparation of1-(3-(2-cyanopropan-2-yl)isoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 125A Step 1: Prepared from ethyl 2-cyano-2-methylpropanoate (3g, 21.25 mmol) according to the method described for4-methyl-3-oxopentanenitrile in Example 122A Step 1, to afford2,2-dimethyl-3-oxopentanedinitrile as a yellow oil (1.40 g, 48%) whichwas used in the next step without further purification. ¹H NMR (300 MHz,CDCl₃) δ 3.98 (s, 2H), 1.60 (s, 6H).

Example 125A Step 2: Prepared from 2,2-dimethyl-3-oxopentanedinitrile(500 mg, 3.68 mmol) and hydroxylamine sulfate (332 mg, 2.02 mmol)according to the method described for 3-isopropylisoxazol-5-amine inExample 122A Step 2. Purification via silica gel chromatography elutingwith 5% to 60% ethyl acetate in hexanes, afforded2-(5-aminoisoxazol-3-yl)-2-methylpropanenitrile as a colorless solid(130 mg, 23%). ¹H NMR (300 MHz, CDCl₃) δ 5.22 (s, 1H), 4.58 (brs, 2H),1.72 (s, 6H); LC-MS (ESI) m/z 152 (M+H)⁺.

Example 125A Step 3: Prepared from2-(5-aminoisoxazol-3-yl)-2-methylpropanenitrile (130 mg, 0.861 mmol)according to the method described for phenyl3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to affordphenyl 3-(2-cyanopropan-2-yl)isoxazol-5-ylcarbamate as a colorless solid(93 mg, 40%). ¹H NMR (300 MHz, CDCl₃) δ 7.82 (brs, 1H), 7.41-7.46 (m,2H), 7.32 (m, 1H), 7.18-7.21 (m, 2H), 6.29 (s, 1H), 1.83 (s, 6H); LC-MS(ESI) m/z 272 (M+H)⁺.

Example 125B: Prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)anilinefrom Example 113A (89 mg, 0.30 mmol) and the carbamate from the previousstep (90 mg, 0.332 mmol) according to the method described for1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)ureain Example 122B, except the reaction mixture was stirred at roomtemperature for 3 h. Purification via silica gel chromatography elutingwith 100% dichloromethane to 10% methanol in dichloromethane afforded1-(3-(2-cyanopropan-2-yl)isoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)ureaas a colorless solid (55 mg, 39%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.51(brs, 1H), 9.12 (brs, 1H), 8.57 (s, 1H), 7.56-7.57 (m, 2H), 7.31-7.45(m, 3H), 7.01 (m, 1H), 6.27 (s, 1H), 4.00 (s, 6H), 1.68 (s, 6H); LC-MS(ESI) m/z 475 (M+H)⁺.

Example 126 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea

3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3mmol) and phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate fromExample 42A (95 mg, 0.36 mmol) were reacted according to the methoddescribed for1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)ureain Example 122B to afford1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)ureaas a colorless solid (63 mg, 45%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.50(brs, 1H), 9.15 (s, 1H), 8.56 (s, 1H), 7.57-7.58 (m, 2H), 7.40-7.45 (m,2H), 7.32 (m, 1H), 7.00 (m, 1H), 6.14 (s, 1H), 3.99-4.00 (2×s, 6H), 1.67(d, J=21 Hz, 6H); LC-MS (ESI) m/z 468 (M+H)⁺.

Example 127 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-methylcyclopropyl)isoxazol-3-yl)urea

Example 127A Step 1: Prepared from methyl1-methylcyclopropane-1-carboxylate (3 g, 26.28 mmol) according to themethod described in Example 122A Step 1 for 4-methyl-3-oxopentanenitrileto afford 3-(1-methylcyclopropyl)-3-oxopentanenitrile as a yellow oil(2.28 g, 71%) which was taken onto the next step without furtherpurification. ¹H NMR (300 MHz, CDCl₃) δ 3.59 (s, 2H), 1.40 (s, 3H),1.33-1.37 (m, 2H), 0.89-0.91 (m, 2H).

Example 127A Step 2: Prepared from3-(1-methylcyclopropyl)-3-oxopentanenitrile (1 g, 8.13 mmol) accordingto the method described for5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine. Purification viasilica gel chromatography eluting with 12% to 60% ethyl acetate inhexanes afforded 5-(1-methylcyclopropyl)isoxazol-3-amine as a colorlesssolid (80 mg, 7%). ¹H NMR (300 MHz, CDCl₃) δ 5.51 (s, 1H), 3.90 (brs,2H), 1.40 (s, 3H), 1.17 (m, 2H), 0.79 (m, 2H); LC-MS (ESI) m/z 139(M+H)⁺.

Example 127A Step 3: Prepared from5-(1-methylcyclopropyl)isoxazol-3-amine (80 mg, 0.58 mmol) according tothe method described for phenyl 3-isopropylisoxazol-5-ylcarbamate inExample 122A Step 3, to afford phenyl5-(1-methylcyclopropyl)isoxazol-3-ylcarbamate as a colorless solid (105mg, 70%). ¹H NMR (300 MHz, CDCl₃) δ 7.87 (brs, 1H), 7.39-7.44 (m, 2H),7.18-7.29 (m, 3H), 6.52 (s, 1H), 1.58 (s, 3H), 1.20-1.24 (m, 2H),0.84-0.87 (m, 2H); LC-MS (ESI) m/z 259 (M+H)⁺.

Example 127B: 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example113A (89 mg, 0.3 mmol) and phenyl5-(1-methylcyclopropyl)isoxazol-3-ylcarbamate (93 mg, 0.36 mmol) werereacted according to the method described for1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)ureain Example 122B to afford1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-methylcyclopropyl)isoxazol-3-yl)ureaas a colorless solid (80 mg, 58%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.57(brs, 1H), 9.01 (brs, 1H), 8.56 (s, 1H), 7.56-7.58 (m, 2H), 7.38-7.43(m, 2H), 7.25 (m, 1H), 6.97 (m, 1H), 6.47 (s, 1H), 3.99-4.00 (2×s, 6H),1.39 (s, 3H), 1.06-1.10 (m, 2H), 0.86-0.90 (m, 2H); LC-MS (ESI) m/z 462(M+H)⁺.

Example 128 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-yl)urea

Example 128A Step 1: Prepared from methyl3-methoxy-2,2-dimethylpropanoate (8 g, 54.7 mmol) according to themethod described in Example 122A Step 1 for4-methyl-3-oxopentanenitrile. Purification via silica gel chromatographyeluting with mixtures of petroleum ether and ethyl acetate afforded5-methoxy-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (2.5 g, 29%).¹H NMR (300 MHz, CDCl₃) δ 3.72 (s, 2H), 3.32-3.33 (m, 5H), 1.18 (s, 6H).

Example 128A Step 2: Prepared from5-methoxy-4,4-dimethyl-3-oxopentanenitrile (500 mg, 3.22 mmol) accordingto the method described for 3-isopropylisoxazol-5-amine in Example 122AStep 2, to afford 3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-amine as aorange oil (380 mg, 69%) which was used in the next step without furtherpurification. ¹H NMR (300 MHz, CDCl₃) δ 5.08 (s, 1H), 4.41 (brs, 2H),3.39 (s, 2H), 3.35 (s, 3H), 1.28 (s, 6H).

Example 128A Step 3: Prepared from3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-amine (100 mg, 0.59 mmol)according to the method described for phenyl3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to affordphenyl 3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-ylcarbamate as an oilthat was not purified further.

Example 128B: 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example113A (40 mg, 0.13 mmol) and phenyl3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-ylcarbamate from theprevious step (50 mg, 0.18 mmol) were reacted according to the methoddescribed for1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)ureain Example 122B. Purification via preparative silica gel thin layerchromatography eluting with 10% methanol in dichloromethane afforded1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-yl)ureaas a pale yellow solid (35 mg, 54%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.17(brs, 1H), 9.05 (brs, 1H), 8.56 (s, 1H), 7.56 (s, 2H), 7.38-7.44 (m,2H), 7.30 (m, 1H), 7.00 (m, 1H), 6.03 (s, 1H), 3.98-4.00 (2×s, 6H), 3.34(s, 3H), 3.22 (s, 2H), 1.20 (s, 6H); LC-MS (ESI) m/z 494 (M+H)⁺.

Example 129 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)urea

Example 129B: The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 g, 0.3mmol) and phenyl 3-(2-methoxyethoxy)-5-(trifluoromethyl)phenylcarbamatefrom Example 117A (160 mg, 0.45 mmol) in the manner described in Example115C. The final product was purified by column chromatography (25-100%EtOAc/hexanes then 5-10% MeOH/DCM) to give1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)urea(150 mg, 0.27 mmol, 90%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.09 (s, 1H), 9.03(s, 1H), 8.57 (s, 1H), 7.61-7.57 (m, 2H), 7.49 (s, 1H), 7.43-7.38 (m,2H), 7.31-7.24 (m, 2H), 6.95 (d, 1H), 6.86 (s, 1H), 4.19-4.11 (m, 2H),4.00 (s, 3H), 3.99 (s, 3H), 3.70-3.63 (m, 2H), 3.31 (s, 3H); LC-MS (ESI)m/z 559 (M+H)⁺.

Example 130 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-yl)urea

Example 130A Step 1: To a mixture of5-methoxy-4,4-dimethyl-3-oxopentanenitrile (1 g, 6.5 mmol) in ethanol(100 mL), was added 96% sodium hydroxide (308 mg, 7.70 mmol). To thiswas added a solution of hydroxylamine hydrochloride (537 mg, 7.70 mmol)in water (100 mL). The resulting solution (pH 7.8) was stirred at 60° C.for 22 h, then cooled to room temperature. To this was addedconcentrated hydrochloric acid (3 mL, 36 mmol) and the mixture refluxed(80° C.) for 1 h. The reaction mixture was concentrated under reducedpressure to remove ethanol and the residue was mixed with 30% sodiumhydroxide (2.1 g). The mixture was shaken with chloroform. Thechloroform layer was washed with water, dried over anhydrous sodiumsulfate and concentrated under reduced pressure to give an oil.Purification via silica gel chromatography afforded5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine as a colorless solid(350 mg, 32%). ¹H NMR (300 MHz, CDCl₃) δ 5.60 (s, 1H), 3.39 (s, 2H),3.32 (s, 3H), 2.94 (brs, 2H), 1.28 (s, 6H); LC-MS (ESI) m/z 171 (M+H)⁺.

Example 130A Step 2: Prepared from5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine (30 mg, 0.176 mmol)according to the method described for phenyl3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to affordphenyl 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate as an oil(50 mg, 98%). ¹H NMR (300 MHz, CDCl₃) δ 8.04 (brs, 1H), 7.42-7.43 (m,2H), 7.31 (m, 1H), 7.18-7.21 (m, 2H), 6.63 (s, 1H), 3.45 (s, 2H), 3.33(s, 3H), 1.35 (s, 6H).

Example 130B: Prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)anilinefrom Example 113A (50 mg, 0.16 mmol) and phenyl5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate from Example130A (50 mg, 0.17 mmol) according to the method described for1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)ureain Example 122B. Purification via preparative silica gel TLC elutingwith 10% methanol in dichloromethane afforded1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-yl)ureaas a colorless solid (38 mg, 44%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.57(brs, 1H), 9.01 (brs, 1H), 8.56 (s, 1H), 7.57-7.58 (m, 2H), 7.38-7.42(m, 2H), 7.25 (m, 1H), 6.97 (m, 1H), 6.50 (s, 1H), 3.99 (s, 6H), 3.38(s, 2H), 3.23 (s, 3H), 1.24 (s, 6H); LC-MS (ESI) m/z 494 (M+H)⁺.

Example 131 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-yl)urea

Example 131A Step 1: A solution of methyl3-hydroxy-2,2-dimethylpropanoate (5.00 g, 38 mmol),N,N-diisopropylethylamine (7.30 g, 57 mmol) andtert-butyldimethylchlorosilane (6.80 g, 45 mmol) in dry DMF (70 mL) wasstirred at room temperature for 12 h. The reaction solution was quenchedwith water (225 mL) and extracted with diethyl ether (3×50 mL). Thecombined organic extracts were washed with water (100 mL), brine (100mL), then dried over MgSO₄. Concentration under reduced pressureafforded methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate ascolorless oil (9.36 g, 100%). It was used in the next step withoutfurther purification. ¹H NMR (300 MHz, CDCl₃) δ 3.64 (s, 3H), 3.55 (s,2H), 1.13 (s, 6H), 0.85 (s, 9H), 0.0 (s, 6H).

Example 131A Step 2: Prepared from methyl3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate (6 g, 24.39 mmol)according to the method described for 4-methyl-3-oxopentanenitrileExample XA Step 1. Purification via silica gel chromatography elutingwith 33% ethyl acetate in petroleum ether afforded5-hydroxy-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (1 g, 29%).¹H NMR (300 MHz, CDCl₃) δ 3.76 (s, 2H), 3.61 (s, 2H), 1.19 (s, 6H).

Example 131A Step 3: Prepared from5-hydroxy-4,4-dimethyl-3-oxopentanenitrile (1 g, 7.90 mmol) according tothe method described for5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine. Purification viarecrystallisation from diethyl ether afforded2-(3-aminoisoxazol-5-yl)-2-methylpropan-1-ol as a colorless solid (600mg, 49%). ¹H NMR (300 MHz, CDCl₃) δ 5.64 (s, 1H), 3.65 (s, 2H), 2.30(brs, 2H), 1.31 (s, 6H).

Example 131A Step 4: Prepared from2-(3-aminoisoxazol-5-yl)-2-methylpropan-1-ol (100 mg, 0.60 mmol)according to the method described for phenyl3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to affordphenyl 5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate as acolorless solid (120 mg, 72%). ¹H NMR (300 MHz, CDCl₃) δ 8.30 (brs, 1H),7.42-7.43 (m, 2H), 7.26 (m, 1H), 7.18-7.21 (m, 2H), 6.65 (s, 1H), 3.67(s, 2H), 1.98 (brs, 1H), 1.32 (s, 6H).

Example 131B: Preparation of final product: Prepared from3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (30 mg,0.10 mmol) and phenyl5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate from theprevious step (41 mg, 0.15 mmol) according to the method described for1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)ureain Example 122B. Purification via preparative TLC eluting with 10%methanol in dichloromethane afforded1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-yl)ureaas a colorless solid (30 mg, 61%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.57(brs, 1H), 8.99 (brs, 1H), 8.56 (s, 1H), 7.56-7.58 (m, 2H), 7.38-7.42(m, 2H), 7.23-7.26 (m, 1H), 6.95-6.98 (m, 1H), 6.49 (s, 1H), 4.95 (brs,1H), 3.98-3.99 (2×s, 6H), 3.43 (s, 2H), 1.20 (s, 6H); LC-MS (ESI) m/z480 (M+H)⁺.

Example 132 Preparation of1-(3-tert-butylisoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 132A: Using the procedure described in Example 113B3-tert-butylisoxazol-5-amine (620 mg, 4.4 mmol) was reacted to affordphenyl 3-tert-butylisoxazol-5-ylcarbamate (1.02 g, 89%) as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 11.81 (bs, 1H), 7.47-7.42 (m, 2H),7.32-7.23 (m, 3H), 6.05 (s, 1H), 1.27 (s, 9H); LC-MS (ESI) m/z 261(M+H)⁺.

Example 132B: The title compound was prepared as described in Example113C with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A(90 mg, 0.3 mmol) and phenyl 3-tert-butylisoxazol-5-ylcarbamate from theprevious step (118 mg, 0.45 mmol) to give1-(3-tert-butylisoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(41 mg, 29%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.19 (s,1H), 9.04 (s, 1H), 8.57 (s, 1H), 7.59-7.56 (m, 2H), 7.44-7.39 (m, 2H),7.30 (d, 1H), 6.98 (d, 1H), 6.04 (s, 1H), 3.99 (s, 6H), 1.25 (s, 9H);LC-MS (ESI) m/z 464 (M+H)⁺.

Example 133 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-isopropylisoxazol-3-yl)urea

Example 133A Step 1: In an oven dried flask equipped with a condenserand an Argon inlet, sodium hydride, 60% in mineral oil, (2.4 g, 61.10mmol) was suspended in anhydrous tetrahydrofuran (26 mL). The suspensionwas refluxed under Argon and a mixture of anhydrous acetonitrile (3.2mL, 61.10 mmol) and methylisobutyrate (4 g, 39.16 mmol) was addeddropwise over fifty minutes. After the addition was complete, themixture was heated at reflux overnight. After cooling to roomtemperature, the mixture was poured into water (150 mL). Diethyl ether(150 mL) was added and the two phases separated. The aqueous layer wasacidified to pH=1 with 10% aqueous hydrochloric acid and the organicsextracted twice with diethyl ether (2×100 mL). The combined organiclayers were dried (MgSO₄), filtered and concentrated under reducedpressure to afford 4-methyl-3-oxopentanenitrile (3.12 g, 72%) as ayellow oil, which was used directly in the next step without furtherpurification. ¹H NMR (300 MHz, CDCl₃) δ 3.54 (s, 2H), 2.86-2.77 (m, 1H),1.19 (d, 6H).

Example 133A Step 2: 4-Methyl-3-oxopentanenitrile was added to a mixtureof ethylene glycol (4.7 mL, 84 mmol) and chlorotrimethylsilane (10.6 mL,84 mmol) in anhydrous dichloromethane (50 mL). The mixture was stirredat 40° C. overnight. After cooling to room temperature a solution of 5%sodium bicarbonate (50 mL) was added, the layer were separated and thewater phase back extracted three times with diethyl ether. The organicswere combined, dried (MgSO₄), filtered and concentrated under reducedpressure. The resulting residue was purified by silica gelchromatography (hexane/ethyl acetate 8:2) to afford2-(2-isopropyl-1,3-dioxolan-2-yl)acetonitrile (3.38 g, 78%) as acolorless oil. ¹H NMR (300 MHz, CDCl₃) δ 4.21-4.16 (m, 2H), 4.07-3.99(m, 2H), 2.69 (s, 2H), 2.08-2.01 (m, 1H), 0.96 (d, 6H).

Example 133A Step 3: To a solution of hydroxylamine hydrochloride (6.3g, 91.7 mmol) in methanol (2.5 mL), liquid ammonia (15.7 mL, 7N inmethanol) was added and the suspension stirred for 30 minutes at roomtemperature. A catalytic amount of 8-hydroxiquinoline was added to themixture, followed by 2-(2-isopropyl-1,3-dioxolan-2-yl)acetonitrile (3.38g, 22 mmol) as a solution in methanol (2.5 mL). The mixture was stirredat 70° C. overnight. After cooling to room temperature, the suspensionwas filtered off and washed with dichloromethane. The solution wasconcentrated under reduced pressure, and reconcentrated three times fromtoluene to affordN′-hydroxy-2-(2-isopropyl-1,3-dioxolan-2-yl)acetimidamide (3.9 g, 94%)as a yellow solid, which was used directly in the next step withoutfurther purification. ¹H NMR (300 MHz, CDCl₃) δ 5.01 (bs, 2H), 4.05-3.94(m, 4H), 2.44 (s, 2H), 2.03-1.94 (m, 1H), 0.95 (d, 6H); LC-MS (ESI) m/z189 (M+H)⁺.

Example 133A Step 4:N′-Hydroxy-2-(2-isopropyl-1,3-dioxolan-2-yl)acetimidamide (1.8 g, 9.57mmol) was dissolved in ethanol (12 ml) and acidified to pH=1 with 37%aqueous hydrochloric acid. The mixture was subjected to microwaveheating at 120° C. for 30 minutes. After concentration under reducedpressure the residue was diluted with dichloromethane, a solution ofsaturated sodium bicarbonate was added until the solution became basic(pH=11) and the organic layer separated. After multiple extractions ofthe water phase with dichloromethane, the organic layers were combined,dried (MgSO₄), filtered and concentrated under reduced pressure. Thecrude material was purified by silica gel chromatography (hexane/ethylacetate 1:1) to afford 5-isopropylisoxazol-3-amine (819 mg, 68%). ¹H NMR(300 MHz, CDCl₃) δ 5.52 (s, 1H), 3.89 (bs, 2H), 2.96-2.91 (m, 1H), 1.27(d, 6H); LC-MS (ESI) m/z 127 (M+H)⁺.

Example 133A Step 5: The procedure described in Example 113B was used,but using 5-isopropylisoxazol-3-amine (816 mg, 6.5 mmol) as the amine,to afford phenyl 5-isopropylisoxazol-3-ylcarbamate (1.24 g, 77%). ¹H NMR(300 MHz, CDCl₃) δ 8.05 (bs, 1H), 7.41 (t, 2H), 7.30-7.18 (m, 3H), 6.55(s, 1H), 3.09-3.02 (m, 1H), 1.3 (d, 6H); LC-MS (ESI) m/z 247 (M+H)⁺.

Example 133B: The title compound was prepared as described in Example113C using 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A(90 mg, 0.3 mmol) and phenyl 5-isopropylisoxazol-3-ylcarbamate from theprevious step (110 mg, 0.45 mmol) to give1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-isopropylisoxazol-3-yl)urea(79 mg, 59%) as a white solid after purification by preparative HPLC(phenylhexyl reverse phase column). ¹H NMR (300 MHz, DMSO-d₆) δ 9.57 (s,1H), 9.01 (s, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.41 (t, 2H) 7.27 (d,1H), 6.99 (d, 1H), 6.49 (s, 1H), 4.00 (s, 6H), 3.01-2.99 (m, 1H), 1.22(d, 6H); LC-MS (ESI) m/z 450 (M+H)⁺.

Example 134 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(5-isopropylisoxazol-3-yl)urea

The title compound was prepared using the procedure described in Example113C with 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline described inExample 115B (94 mg, 0.3 mmol) and phenyl5-isopropylisoxazol-3-ylcarbamate described in Example 133A (110 mg,0.45 mmol). Precipitation of the desired product detected completion ofreaction. The solid was filtered off and washed with diethyl ether togive1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(5-isopropylisoxazol-3-yl)urea(96.26 mg, 69%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.57 (s, 1H),9.02 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.53-7.42 (m, 2H), 7.36-7.27(m, 3H), 6.51 (s, 1H), 3.99 (s, 6H), 3.04-3.00 (m, 1H), 1.23 (d, 6H);LC-MS (ESI) m/z 466 (M+H)⁺.

Example 135 Preparation of1-(5-cyclopentylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 135A Step 1: According to the procedure described in Example133A Step 1 methyl cyclopentanecarboxylate (4 g, 31.25 mmol), anhydrousacetonitrile (2.55 mL, 48.75 mmol) and sodium hydride, 60% in mineraloil, (1.95 g, 48.75 mmol) in anhydrous tetrahydrofuran (25 mL) werereacted to afford 3-cyclopentyl-3-oxopropanenitrile (3.97 g, 93%) asyellow oil, which was used directly in the next step without furtherpurification. ¹H NMR (300 MHz, CDCl₃) δ 3.5 (s, 2H), 3.13-3.02 (m, 1H),1.95-1.62 (m, 8H).

Example 135A Step 2: According to the procedure described in Example133A Step 2,3-cyclopentyl-3-oxopropanenitrile (2 g, 14 mmol) was addedto a mixture of ethylene glycol (2.4 mL, 44 mmol) andchlorotrimethylsilane (5.5 mL, 44 mmol) to give2-(2-cyclopentyl-1,3-dioxolan-2-yl)acetonitrile (1.5 g, 60%). ¹H NMR(300 MHz, CDCl₃) δ 4.23-4.15 (m, 2H), 4.12-4.01 (m, 2H), 2.72 (s, 2H),2.42-2.30 (m, 1H), 1.81-1.45 (m, 8H).

Example 135A Step 3: According to the procedure described in Example133A Step 3,2-(2-cyclopentyl-1,3-dioxolan-2-yl)acetonitrile (1.5 g, 8.3mmol) was reacted with hydroxylamine hydrochloride (3.17 g, 45.5 mmol)and liquid ammonia (7.8 mL, 7N in methanol), to afford2-(2-cyclopentyl-1,3-dioxolan-2-yl)-N′-hydroxyacetimidamide, which wasused directly in the next step without further purification. ¹H NMR (300MHz, CDCl₃) δ 5.11 (bs, 2H), 4.20-3.95 (m, 4H), 2.38 (s, 2H), 2.33-2.22(m, 1H), 1.73-1.41 (m, 8H); LC-MS (ESI) m/z 215 (M+H)⁺

Example 135A Step 4: According to the procedure described for5-isopropylisoxazol-3-amine in Example 133A Step 4,2-(2-cyclopentyl-1,3-dioxolan-2-yl)-N′-hydroxyacetimidamide (1.99 g, 93mmol) was dissolved in ethanol (2 mL) and acidified with 37% aq.hydrochloric acid to give 5-cyclopentylisoxazol-3-amine (875 mg, 62%) asa white solid. ¹H NMR (300 MHz, CDCl₃) δ 5.52 (s, 1H), 3.86 (bs, 2H),3.09-3.04 (m, 1H), 2.04 (d, 2H), 1.75-1.62 (m, 6H); LC-MS (ESI) m/z 153(M+H)⁺.

Example 135A Step 5: 5-Cyclopentylisoxazol-3-amine (875 mg, 5.75 mmol)was reacted according to the procedure described in Example 113B toafford phenyl 5-isopropylisoxazol-3-ylcarbamate (1.4 g, 89%) as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 7.97 (bs, 1H), 7.42 (t, 2H), 7.29-7.18(m, 3H), 6.54 (s, 1H), 3.19-3.12 (m, 1H), 2.10-2.04 (m, 2H), 1.78-1.58(m, 6H); LC-MS (ESI) m/z 273 (M+H)⁺.

Example 135B: The title compound was prepared as described in Example113C by using compound 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline fromExample 113A (95 mg, 0.32 mmol) and the phenyl5-isopropylisoxazol-3-ylcarbamate intermediate from the previous step(130 mg, 0.48 mmol) to give1-(5-cyclopentylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(80.60 mg, 53%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s,1H), 9.03 (s, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.41 (t, 2H), 7.26 (d,1H), 6.97 (d, 1H), 6.50 (s, 1H), 4.00 (s, 6H), 3.21-3.00 (m, 1H),1.66-1.64 (m, 2H), 1.20-1.18 (m, 6H); LC-MS (ESI) m/z 476 (M+H)⁺.

Example 136 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(2-fluoropropan-2-yl)isoxazol-3-yl)urea

Example 136A Step 1: To a stirred solution of4-fluoro-4-methyl-3-oxopentanenitrile (1 g, 7.75 mmol) in dry diethylether (150 mL) at 0° C., was added dropwise (trimethylsilyl)diazomethane(4.65 mL of a 2.0 M solution in diethyl ether, 9.30 mmol). After warmingto room temperature the reaction mixture was stirred for a further 15 h.The reaction mixture was concentrated under reduced pressure to afford4-fluoro-3-methoxy-4-methylpent-2-enenitrile as a yellow oil (1 g, 91%)which was taken on to the next step without further purification. ¹H NMR(300 MHz, CDCl₃) δ 4.89 (s, 1H), 4.23 (s, 3H), 1.47 (d, J=21 Hz, 6H).

Example 136A Step 2: To dry methanol (10 mL) at room temperature, wasadded portionwise sodium metal (145 mg, 6.30 mmol). After all metal haddissolved, the reaction mixture was cooled to 0° C. and hydroxylaminehydrochloride (438 mg, 6.30 mmol) was added in one portion. The reactionmixture was stirred for 15 mins before adding a solution of4-fluoro-3-methoxy-4-methylpent-2-enenitrile (500 mg, 3.50 mmol) in drymethanol (3 mL). The mixture was heated at 70° C. for 16 h. Concentratedhydrochloric acid (0.8 mL, 9.6 mmol) was added and the reaction mixturestirred at 80° C. for 30 mins. After cooling to room temperature, thereaction was concentrated under reduced pressure to give an orange foamwhich was dissolved in water (50 mL) and adjusted to pH 10 using aq 1MNaOH solution. The aqueous layer was then extracted with dichloromethane(3×50 mL) and the combined organic layers were washed with brine (50mL), dried over MgSO₄ and concentrated under reduced pressure to give ayellow oil. The crude product was purified by silica gel chromatographyeluting with 12% ethyl acetate in hexanes to 100% ethyl acetate toafford 5-(2-fluoropropan-2-yl)isoxazol-3-amine as a cream solid (64 mg,13%). ¹H NMR (300 MHz, CDCl₃) δ 5.82 (s, 1H), 4.08 (brs, 2H), 1.71 (d,J=21 Hz, 6H); LC-MS (ESI) m/z 145 (M+H)⁺.

Example 136A Step 3: Prepared from5-(2-fluoropropan-2-yl)isoxazol-3-amine (40 mg, 0.278 mmol) and4-chlorophenyl chloroformate (54 mg, 0.28 mmol) according to theprocedure described in Example 122A Step 3, to afford 4-chlorophenyl5-(2-fluoropropan-2-yl)isoxazol-3-ylcarbamate as a colorless solid (83mg, 100%). ¹H NMR (300 MHz, CDCl₃) δ 8.11 (brs, 1H), 7.36-7.40 (m, 2H),7.12-7.17 (m, 2H), 6.83 (s, 1H), 1.76 (d, J=21 Hz, 6H); LC-MS (ESI) m/z299 (M+H)⁺.

Example 136B: 3-(6,7-Dimethoxyquinazolin-4-yloxy)aniline from Example113A (90 mg, 0.302 mmol) and 4-chlorophenyl5-(2-fluoropropan-2-yl)isoxazol-3-ylcarbamate from the previous step (90mg, 0.302 mmol) were reacted according to the procedure described inExample 122B, except the reaction mixture was stirred at roomtemperature for 3 h. The crude material was purified via silica gelchromatography (0%-10% methanol in dichloromethane) to afford1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(2-fluoropropan-2-yl)isoxazol-3-yl)ureaas a colorless solid (37 mg, 26%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.75(brs, 1H), 9.04 (brs, 1H), 8.56 (s, 1H), 7.56-7.58 (m, 2H), 7.40-7.41(m, 2H), 7.29 (m, 1H), 7.00 (m, 1H), 6.86 (s, 1H), 4.00 (s, 6H), 1.72(d, J=21 Hz, 6H); LC-MS (ESI) m/z 468 (M+H)⁺.

Example 137 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea

Example 137A Step 1: To a slurry of NaH (432 mg, 18 mmol) in THF (40 mL)heated at reflux was added dropwise over 10 minutes a solution of methyl1-(trifluoromethyl)cyclopropanecarboxylate (2.0 g, 11.9 mmol) inacetonitrile (940 uL, 12 mmol) and the mixture heated at refluxovernight. After cooling to room temperature, the reaction waspartitioned between ether and H₂O, the aqueous layer acidified with 1NHCl_((aq)), extracted with ether, and the combined org layers washedwith brine, dried over MgSO₄, filtered, concentrated in vacuo, andpurified by column chromatography (5-40% EtOAc/hexanes) to give3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile (1.04 g, 5.88mmol, 49%). LC-MS (ESI) m/z 178 (M+H)⁺.

Example 137A Step 2: To3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile (230 mg, 1.3mmol) in EtOH (5 mL, 200 proof) was added H₂O (3.7 mL), 1N NaOH_((aq))(1.3 mL), and phenylhydrazine hydrochloride (188 mg, 1.3 mmol) and themixture heated at 90° C. overnight. After cooling to room temperature,the mixture was diluted with H2O, extracted with EtOAc, the org layerconcentrated in vacuo, and purified by column chromatography (5-25%EtOAc/hexanes) to give1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (150 mg,0.56 mmol, 43%). LC-MS (ESI) m/z 268 (M+H)⁺.

Example 137A Step 3: Using the procedure described in Example 118A,1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (150 mg,0.56 mmol) was used in place of the aniline to give phenyl1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-ylcarbamate(129 mg, 0.33 mmol, 59%). LC-MS (ESI) m/z 388 (M+H)⁺.

Example 137B: The title compound was prepared from phenyl1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-ylcarbamatedescribed in Example 137A (129 mg, 0.33 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline described in Example 113A(100 mg, 0.33 mmol) using the procedure described in Example 115C. Thecrude product was purified by column chromatography (25-100%EtOAc/hexanes) to give1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea(139 mg, 0.24 mmol, 71%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 8.61(s, 1H), 8.55 (s, 1H), 7.63-7.51 (m, 6H), 7.48 (d, 1H), 7.39 (s, 1H),7.37 (t, 1H), 7.17 (d, 1H), 6.93 (d, 1H), 6.55 (s, 1H), 4.00 (s, 3H),3.98 (s, 3H), 1.31 (d, 4H); LC-MS (ESI) m/z 591 (M+H)⁺.

Example 138 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(4-methoxy-3-(trifluoromethyl)phenyl)urea

Example 138A: To a solution of 4-methoxy-3-trifluoromethyl aniline (500mg, 2.62 mmol) in 20 mL of tetrahydrofuran was added potassium carbonate(470 mg, 3.4 mmol), followed by phenyl chloroformate (532 mg, 3.4 mmol).This solution was stirred overnight at room temperature, thenconcentrated and purified by silica gel chromatography using a gradientof ethyl acetate/hexanes 0-20% to afford phenyl4-methoxy-3-(trifluoromethyl)phenylcarbamate as a white solid. ¹H NMR(300 MHz, CDCl₃) 7.75-7.65 (m, 2H), 7.60-7.40 (m, 2H), 7.27-7.19 (m,3H), 7.00-6.93 (m, 2H), 3.89 (s, 3H).

Example 138B: In a sealed reaction vessel3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (100 mg,0.34 mmol) was dissolved in 10 ml of dry THF and diisopropylethyl amine(90 μL, 0.51 mmol) and DMAP (50 mg, 0.40 mmol) was added followed bycarbamate from the previous step (159 mg, 0.51 mmol) and the reactionheated to 80° C. overnight. The reaction was concentrated to dryness andthen triturated with ethyl acetate, and filtered to afford1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(4-methoxy-3-(trifluoromethyl)phenyl)urea(67.5 mg, 34% yield). ¹H (DMSO-d₆) δ 8.97 (d, 2H), 8.56 (s, 1H), 7.83(s, 1H), 7.70-7.60 (m, 3H), 7.5-7.2 (m, 4H), 6.93 (m, 1H), 3.98 (s, 6H),3.83 (s, 3H) LCMS (ESI) m/z 582 (M+H)⁺.

Example 139 Preparation of1-(4-methoxy-3-(trifluoromethyl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

According to the procedure for Example 138B,4-methoxy-3-(trifluoromethyl)phenylcarbamate described in Example 138A(104 mg, 0.34 mmol) was reacted with3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline described inExample 117B (100 mg, 0.28 mmol). To this solution was addeddiisopropylethyl amine (74 μL, 0.42 mmol) and DMAP (20.0 mg, 0.16 mmol).The reaction was concentrated to dryness and partitioned between waterand dichloromethane, and extracted twice. The combined extracts werewashed with brine, dried over magnesium sulfate, filtered andconcentrated. The crude oil was purified by silica gel chromatography(methanol/dichloromethane 0-5%) to give1-(4-methoxy-3-(trifluoromethyl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)ureaas a white solid (18.6 mg, 10% yield). ¹H (DMSO-d₆) 8.90 (s, 1H), 8.80(s, 1H), 8.60 (s, 1H), 7.85 (s, 1H), 7.60 (m, 3H), 7.40 (m, 2H), 7.25(m, 2H), 6.90 (d, 1H), 4.35 (m, 2H), 3.99 (s, 3H), 3.80 (s, 3H), 3.75(m, 2H), 3.30 (s, 3H). LCMS (ESI) m/z 559 (M+H)⁺.

Example 140 Preparation of1-(3-chloro-5-(trifluoromethyl)phenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 140A: According to the procedure described in Example 113B,3-chloro-5-trifluoromethylaniline (500 mgs, 2.56 mmoles) in 20 ml oftetrahydrofuran was treated with potassium carbonate (460 mgs, 3.33mmoles) and phenyl chloroformate (521 mgs, 3.33 mmoles). After stirringovernight at room temperature the solution was filtered, andconcentrated to a solid. Trituration with ethyl acetate gave phenyl3-chloro-5-(trifluoromethyl)phenyl carbamate as a white solid usedwithout further purification. ¹H NMR (300 MHz, CDCl₃) δ 7.75 (s, 1H),7.64 (s, 1H), 7.45 (m, 2H), 7.35 (s, 1H), 7.2-7.1 (m, 2H), 7.0 (m, 1H)

Example 140B: The resulting carbamate was reacted as described inExample 138B and isolated and purified to give the title compound (26mg, 15%). ¹H (DMSO-d₆) 9.30 (s, 1H), 9.15 (s, 1H), 8.56 (s, 1H), 7.83(d, 2H), 7.59 (m, 2H), 7.40 (m, 3H), 7.30 (m, 1H), 6.9 (m, 1H), 4.0 (s,6H) LCMS (ESI) m/z 519 (M+H)⁺.

Example 141 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(4-(trifluoromethyl)pyridin-2-yl)urea

Example 141A. According to the procedure described in Example 113B,2-amino-4-trifluoromethylpyridine (462 mg, 2.85 mmoles) was dissolved in20 ml of tetrahydrofuran. To this solution was added potassium carbonate(511 mgs, 3.7 mmoles) followed by phenyl chloroformate (521 mgs, 3.33mmoles). The mixture was concentrated and purified according to theprocedure in Example 138 to afford phenyl4-(trifluoromethyl)pyridin-2-ylcarbamate. ¹H NMR (300 MHz, CDCl₃) δ 9.53(s, 1H), 8.56 (m, 1H), 8.38 (s, 1H), 7.6-7.4 (m, 2H), 7.3-7.2 (m, 2H),6.8 (m, 1H).

Example 141B. The resulting carbamate (144 mg, 0.51 mmol) was reacted asdescribed in Example 138B and isolated and purified to give 55 mg offinal product. ¹H (DMSO-d₆) 9.95 (s, 1H), 9.76 (s, 1H), 8.56 (m, 2H)8.01 (s, 1H), 7.64 (d, 2H), 7.5-7.3 (m, 4H), 6.98 (m, 1H), 3.98 (s, 6H)LCMS (ESI) m/z 486 (M+H)⁺.

Example 142 Preparation of1-(2-chloro-5-(trifluoromethyl)phenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 142A: According to the procedure described in Example 113B,2-chloro-5-trifluoromethylaniline (500 mg, 2.56 mmoles) was dissolved in20 mL of tetrahydrofuran. To this solution was added potassium carbonate(460 mg, 3.33 mmoles) followed by phenyl chloroformate (521 mg, 3.33mmoles). This was isolated and purified according to the procedure inExample 140A to afford 2-chloro-5-(trifluoromethyl)phenylcarbamate. ¹HNMR (300 MHz, CDCl₃) δ 8.58 (s, 1H), 7.7-7.3 (m, 7H)

Example 142B: The resulting carbatmate (160 mg, 0.51 mmol) was reactedas described in the procedure for Example 138 Band isolated and purifiedto give 83 mg of final product. ¹H NMR (300 MHz, DMSO-d₆) δ 9.76 (s,1H), 8.7-8.5 (m, 3H), 7.74 (d, 1H), 7.64 (m, 1H), 7.57 (s, 1H), 7.5-7.3(m, 3H), 7.24 (m, 1H), 7.00 (m, 1H), 4.00 (s, 6H). LCMS (ESI) m/z 519(M+H)⁺.

Example 143 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(4-(trifluoromethyl)pyrimidin-2-yl)urea

Example 143A: According to the procedure described in Example 113B, to asolution of 4-(trifluoromethyl)pyrimidin-2-amine (500 mg, 3.1 mmoles) in20 mL of tetrahydrofuran was added potassium carbonate (533 mg, 4mmoles) followed by phenyl chloroformate (626 mg, 4 mmoles). The mixturewas stirred at room temperature overnight. After 24 hours, andadditional portion of phenyl chloroformate was added and the reactionheated to 60° C. for 3 days. This solution was concentrated to drynessand purified by silica chromatography (eluted with a gradient of 0-5%ethyl acetate/dichloromethane) to afford phenyl4-(trifluoromethyl)pyrimidin-2-ylcarbamate. ¹H NMR (300 MHz, DMSO-d₆) δ11.50 (s, 1H), 9.05 (s, 1H), 7.69 (m, 1H), 7.46 (m, 2H), 7.25 (m, 3H).

Example 143B: The resulting carbamate (144 mg, 0.51 mmol) was reacted asdescribed in Example 138B to give 93 mg of final product. ¹H NMR (300MHz, DMSO-d₆) δ 11.13 (s, 1H), 10.72 (s, 1H), 9.03 (s, 1H), 8.56 (s,1H), 7.7-7.4 (m, 6H), 7.04 (m, 1H), 3.99 (s, 6H). LCMS (ESI) m/z 487(M+H)⁺.

Example 144 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylphenyl)urea

Example 144A. According to the procedure described in Example 113B,4-(trifluoromethyl)pyrimidin-2-amine (500 mg, 3.1 mmoles) in 20 mL oftetrahydrofuran. To this solution was added potassium carbonate (533 mg,4 mmoles) followed by phenyl chloroformate (626 mg, 4 mmoles). This wasstirred at room temperature overnight. After 24 hours, and additionalportion of phenyl chloroformate was added and the reaction heated to 60C for 3 days. This solution was concentrated to dryness and purified bysilica chromatography (eluting with a gradient of 0-5% ethylacetate/dichloromethane) to afford phenyl 3-isopropylphenylcarbamate asa solid. ¹H NMR (300 MHz, CDCl₃) δ 7.6-7.0 (m, 9H), 2.9 (m, 1H), 1.35(m, 6H).

Example 144B. The resulting carbamate (144 mg, 0.51 mmol) was reacted asin Example 138B to give 24 mg of final product. ¹H NMR (300 MHz,DMSO-d₆) δ 8.61 (s, 1H), 7.9 (s, 1H), 7.7-7.5 (m, 3H), 7.5-7.2 (m, 3H),7.15 (m, 1H), 7.1-6.8 (m, 4H), 4.05 (s, 6H), 2.80 (m, 1H), 1.17 (m, 6H).LCMS (ESI) m/z 459 (M+H)⁺.

Example 145 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(4-(3-methoxy-3-methylbutoxy)-3-(trifluoromethyl)phenyl)urea

Example 145A. According to the procedure described in Example 113B,4-(3-methoxy-3-methylbutoxy)-3-(trifluoromethyl)aniline (490 mg, 1.77mmoles) was dissolved in 20 mL of dry tetrahydrofuran. To this solutionwas added potassium carbonate (318 mg, 2.30 mmoles) followed by phenylchloroformate (360 mg, 2.30 mmoles). The mixture was stirred overnightat room temperature, then purified with silica gel chromatography (usinga gradient of 0-30% ethyl acetate/hexanes) to afford phenyl4-(3-methoxy-3-methylbutoxy)-3-(trifluoromethyl)-phenylcarbamate as ayellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.58 (m, 2H), 7.40 (m, 2H),7.35-7.1 (m, 4H), 6.9 (m, 1H), 4.10 (m, 2H), 3.22 (s, 3H), 2.1 (m, 2H),2.1 (m, 2H).

Example 145B. The resulting carbamate (202 mg, 0.51 mmol) was reacted asin Example 138B, isolated and purified by HPLC (using a reversed phasephenyl hexyl column and a gradient of 40-70% ACN/water over 60 minutes)to afford 82.5 mg of the title compound as a solid. ¹H NMR (300 MHz,DMSO-d₆) δ 9.05 (s, 1H), 8.95 (s, 1H), 8.55 (s, 1H), 7.85 (s, 1H), 7.55(m, 3H), 7.35 (m, 2H), 7.25 (m, 2H), 6.90 (m, 1H), 4.15 (m, 2H) 4.00 (s,6H), 3.10 (s, 3H), 1.9 (m, 2H) 1.16 (s, 6H). LCMS (ESI) m/z 601 (M+H)

Example 146 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(6-(trifluoromethyl)pyrimidin-4-yl)urea

Example 146A. According to the procedure described in Example 113B,6-(trifluoromethyl)pyrimidin-4-amine (480 mg, 2.94 mmoles) was dissolvedin 20 mL of tetrahydrofuran. To this solution was added potassiumcarbonate (528 mg, 3.82 mmoles), followed by phenyl chloroformate (598mg, 3.82 mmoles). An additional equivalent of phenyl chloroformate wasadded after stirring overnight and the reaction heated to 60° C. for 2days. The crude product was purified to afford phenyl6-(trifluoromethyl)pyrimidin-4-ylcarbamate as a white solid. ¹H NMR (300MHz, CDCl₃) δ 10.12 (s, 1H), 9.13 (s, 1H), 8.46 (s, 1H), 7.7-7.2 (m, 5H)

Example 146B. The resulting carbamate (144 mg, 0.51 mmol) was reacted asdescribed in Example 138B, and isolated and purified to give 15 mg offinal product. ¹H NMR (300 MHz, DMSO-d₆) δ 10.26 (s, 1H), 9.80 (s, 1H),9.01 (s, 1H), 8.56 (s, 1H), 7.62 (m, 2H), 7.5-7.3 (m, 3H), 7.08 (m, 1H),3.99 (s, 6H). LCMS (ESI) m/z 487 (M+H)

Example 147 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)urea

Example 147A Step 1: In a round bottomed flask sodium hydride (138 mg,5.7 mmol) was suspended in 20 mL of dry tetrahydrofuran and cooled to 0°C. To this suspension was added 2-methoxyethanol (364 mg, 4.8 mmol)dropwise and the reaction stirred for 30 minutes. A solution of2-fluoro-4-nitro-1-trifluoromethyl-benzene (1.0 g, 4.8 mmol) wasprepared with 1 mL of dry tetrahydrofuran and added to the sodiumhydride solution dropwise. This was stirred overnight while warming toroom temperature. The solution was then concentrated to dryness andpartitioned between ethyl acetate and water, then extracted twice. Theorganic layers were dried over magnesium sulfate, filtered andconcentrated. The crude oil was purified by silica gel chromatography(using a gradient of 0-10% ethyl acetate/hexane). The major peak wascollected, concentrated to a solid, and then triturated with hexane, andfiltered to give 2-(2-methoxy-ethoxy)-4-nitro-1-trifluoromethyl-benzene(711 mg, 47% yield). ¹H (300 MHz, DMSO-d₆) δ 8.0 (s, 1H), 7.9 (s, 2H),4.4 (m, 2H), 3.7 (m, 2H), 3.3 (s, 3H)

Example 147A Step 2: The2-(2-methoxy-ethoxy)-4-nitro-1-trifluoromethyl-benzene from the previousstep was dissolved in 5 ml of ethyl acetate to which 10% palladium oncarbon was added. The flask was evacuated three times and flushed withhydrogen. After stirring under hydrogen overnight at room temperaturethe solution was filtered and concentrated to afford3-fluoro-4-trifluoromethyl-phenylamine (610 mg, 97%). ¹H NMR (300 MHz,DMSO-d₆) δ 7.18 (d, 1H), 6.3 (s, 1H), 6.1 (d, 1H), 5.8 (s, 2H), 4.0 (m,2H), 3.6 (m, 2H), 3.3 (s, 3H).

Example 147A Step 3: The amine from the previous step (610 mg, 2.6 mmol)was dissolved in tetrahydrofuran and potassium carbonate (466 mg, 3.4mmol) was added. To this solution was added phenyl chloroformate (447mg, 2.9 mmol) and the solution was stirred overnight at roomtemperature. The solution was then filtered through celite,concentrated, and then partitioned between dichloromethane and water,then extracted with an additional portion of dichloromethane. Theextracts were combined, dried over magnesium sulfate, filtered andconcentrated to give phenyl3-(2-methoxyethoxy)-4-(trifluoromethyl)phenylcarbamate as a solid (820mg, 88%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.6 (s, 1H), 7.6 (d, 1H), 7.4 (m,3H), 7.3 (m, 3H), 7.1 (d, 1H), 4.1 (m, 2H), 3.7 (m, 2H), 3.3 (d, 3H)

Example 147B: As described in Example 113C,3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (90 mg, 0.3mmol) in THF (5 mL) was treated with N,N-diisopropylethylamine (78 μl,0.45 mmol), 4-(dimethylamino)pyridine (4 mg, 0.03 mmol) and phenyl3-(2-methoxyethoxy)-4-(trifluoromethyl)phenylcarbamate (161 mg, 0.45mmol). The reaction mixture was heated to 50° C. for 3 h. After removalof the solvent, the crude material was purified by silica gelchromatography (ethyl acetate/dichloromethane 1:1) to afford1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)urea(109.5 mg, 65%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.14 (s, 1H),9.02 (s, 1H), 8.57 (s, 1H), 7.59 (d, 2H), 7.50-7.38 (m, 2H), 7.43-7.38(m, 2H), 7.27 (d, 1H), 7.04 (d, 1H), 6.96 (d, 1H), 4.17-4.14 (m, 2H),4.04 (s, 6H), 3.69-3.67 (m, 2H), 3.34 (s, 3H); LC-MS (ESI) m/z 559(M+H)⁺.

Example 148 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)urea

The title compound was prepared according to the procedure described inExample 147B by using 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline fromExample 115B (95 mg, 0.3 mmol) and phenyl3-(2-methoxyethoxy)-4-(trifluoromethyl)phenylcarbamate described inExample 147A (161 mg, 0.45 mmol). The reaction was stirred at 50° C.overnight. After removal of the solvent, dichloromethane was added andthe precipitating solid filtered off, washed with DCM and dried to give1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)urea(78 mg, 45%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (s, 1H), 9.03(s, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.55-7.42 (m, 4H), 7.35 (d, 2H),7.28 (d, 1H), 7.05 (d, 1H), 4.18-4.15 (m, 2H), 4.00 (s, 6H), 3.69-3.68(m, 2H), 3.31 (s, 3H); LC-MS (ESI) m/z 575 (M+H)⁺.

Example 149 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(morpholine-4-carbonyl)-5-(trifluoromethyl)phenyl)urea

Example 149A Step 1. In a round bottomed flask,3-nitro-5-trifluoromethylbenzoic acid (5.0 g, 21.3 mmoles) was dissolvedin 40 mL of dry DMF, to this solution was added hydroxybenzotriazole(5.8 g, 42.5 mmoles) and EDCI (8.2 g, 42.5 mmoles) and the solutionstirred for 1 hour at room temperature. At the end of this timemorpholine (2.2 g. 25.5 mmoles) was added and the reaction stirredovernight. The solution was then concentrated to dryness, andpartitioned between water and ethyl acetate. The aqueous layer wasextracted with ethyl acetate and the combined extracts dried withmagnesium sulfate, filtered and concentrated. Chromatography with silicagel and eluting with a ethyl acetate/hexane gradient of 0-35% over 80minutes gave morpholin-4-yl-(3-nitro-5-trifluoromethyl-phenyl)-methanone(1.8 g). ¹H NMR (300 MHz, DMSO-d₆) δ 8.6 (d, 2H), 8.3 (s, 1H), 3.8-3.6(bm, 4H), 3.56 (b, 2H), 3.33 (bs, 2H).

Example 149A Step 2.Morpholin-4-yl-(3-nitro-5-trifluoromethyl-phenyl)-methanone (800 mg, 2.6mmoles) from the previous step was dissolved in 40 mL of ethyl acetate.To this solution was added 10% palladium on carbon, the reaction wasstirred under hydrogen at room temperature overnight. The solutionfiltered through celite and concentrated to give3-(morpholine-4-carbonyl)-5-(trifluoromethyl)phenylamine (688 mg). ¹HNMR (300 MHz, DMSO-d₆) δ 6.90 (s, 1H), 6.75 (d, 2H), 5.6 (b, 6H).

Example 149A Step 3:3-(Morpholine-4-carbonyl)-5-(trifluoromethyl)phenylamine (688 mg, 2.5mmoles) was dissolved in tetrahydrofuran and potassium carbonate (451mg, 3.3 mmoles) was added followed by phenyl chloroformate (432 mg, 2.76mmoles) and the solution stirred overnight at room temperature. Thissolution was filtered through celite and concentrated to a solid. Thiswas partitioned between dichloromethane and brine, extracted twice. Theextracts were combined and dried with magnesium sulfate, filtered andconcentrated to a solid. The solid was triturated with ether, the solidcollected by filtration to afford phenyl3-(morpholine-4-carbonyl)-5-(trifluoromethyl)phenyl carbamate. ¹H NMR(300 MHz, DMSO-d₆) δ 10.7 (s, 1H), 7.98 (s, 1H), 7.77 (s, 1H), 7.3 (m,3H), 7.2 (m, 3H), 3.6 (bm, 6H)

Example 149B. The resulting carbamate (180 mg, 0.45 mmol) was reacted asdescribed in Example 138B. Isolation and purification was accomplishedusing silica gel chromatography (0-100% ethyl acetate/hexane) to affordthe title compound (78 mg, 29% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 9.25(s, 1H), 9.13 (s, 1H), 8.57 (s, 1H), 8.00 (s, 1H), 7.66 (s, 1H), 7.60(d, 2H), 7.38 (m, 2H), 7.30 (m, 2H), 6.95 (m, 1H), 4.10 (s, 6H), 3.63(m, 6H), 3.2 (d, 2H). LCMS (ESI) m/z 598 (M+H)⁺.

Example 150 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)urea

Example 150A Step 1: In a round bottomed flask,2-fluoro-4-nitro-1-trifluoromethyl-benzene (1.00 g, 4.78 mmol) wasdissolved in 10 mL of methanol. To this solution was added 10% palladiumon carbon (100 mg) and the solution was stirred overnight at roomtemperature under hydrogen (1 atm). The solution was filtered andconcentrated to afford 3-fluoro-4-trifluoromethyl-phenylamine. ¹H NMR(300 MHz, DMSO-d₆) δ 7.3 (m, 1H), 6.6 (d, 2H), 6.2 (s, 2H)

Example 150A Step 2: The above amine (600 mg, 3.35 mmol) was dissolvedin 10 ml of dry DMF. To this solution was added potassium carbonate (603mg, 4.36 mmol) followed by the addition of phenyl chloroformate (577 mg,3.69 mmol) as a DMF solution dropwise, and the reaction stirredovernight at room temperature. The solution was filtered andconcentrated to an oil. The oil was purified by silica gelchromatography (using a 10-50% ethyl acetate/hexane gradient) to give584 mg of phenyl 3-fluoro-4-(trifluoromethyl)phenylcarbamate. ¹H NMR(300 MHz, DMSO-d₆) δ 10.9 (s, 1H), 7.7 (m, 1H), 7.6 (d, 1H) 7.4 (m, 3H),7.2 (m, 2H)

Example 150B: The procedure described in Example 138B was used to reactthe carbamate intermediate from above (135 mg, 0.45 mmol) with3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3mmol). To this solution was added diisopropylethyl amine (58 mg, 0.45mmol) and DMAP (3.7 mg, 0.03 mmol). Isolation and purification wasaccomplished using silica gel chromatography eluting with a 10-50% ethylacetate/dichloromethane gradient to give the title compound (112 mg, 74%yield). ¹H NMR (300 MHz, DMSO-d₆) δ 9.43 (s, 1H), 9.32 (s, 1H), 8.57 (s,1H), 7.70 (m, 4H), 7.40 (m, 2H), 7.30 (m, 2H), 6.9 (m, 1H), 4.00 (s,6H). LCMS (ESI) m/z 503 (M+H)⁺.

Example 151 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)urea

Example 151A Step 1: In a round bottomed flaskmorpholino(3-nitro-5-(trifluoromethyl)phenyl)methanone (1.60 g, 5.25mmol) was dissolved in 8 mL of anhydrous THF and cooled to 0 C. To thissolution, a 2 M solution of Borane-dimethyl sulfide (10.5 mL, 21 mmol)in THF was added dropwise. The reaction was stirred overnight whilewarming to room temperature. The solution was then concentrated to anoil. This was partitioned between dichloromethane and water, thenbasified with 1 M sodium hydroxide solution, and extracted twice. Theextracts were combined, washed with water and brine. They were thendried over magnesium sulfate, filtered and concentrated and purified bysilica gel chromatography (using a 0-50% ethyl acetate/hexane gradient)to afford 4-(3-nitro-5-trifluoromethyl-benzyl)-morpholine (409 mg, 27%yield). ¹H NMR (DMSO-d₆) δ 8.46 (s, 1H), 8.4 (s, 1H), 8.15 (s, 1H), 3.7(s, 2H), 3.6 (m, 4H), 2.4 (s, 4H).

Example 151A Step 2: The nitro compound from the previous step wasdissolved in 6 ml of ethyl acetate, to this solution 10% palladium oncarbon was added. The solution was evacuated and purged with hydrogenthree times and stirred overnight at room temperature. The reaction wasfiltered and concentrated to give3-morpholin-4-ylmethyl-5-trifluoromethyl-phenylamine (350 mg, 95%yield). ¹H NMR (DMSO-d₆) δ 6.78 (s, 1H), 6.70 (m, 2H), 5.6 (s, 2H), 4.0(m, 4H), 3.58 (d, 2H), 2.22 (m, 4H); LCMS (ESI) m/z 233 (M+H)⁺.

Example 151A Step 3: The amine (350 mg, 1.3 mmol) was dissolved in 8 mlof dry THF, and potassium carbonate (242 mg, 1.7 mmol) was addedfollowed by phenyl chloroformate (232 mg, 1.8 mmol). The reaction wasstirred overnight at room temperature. The reaction was filtered throughcelite and concentrated to dryness. The resulting oil was partitionedbetween ethyl acetate and water and extracted twice. The resultingextracts were combined and dried over magnesium sulfate, filtered andconcentrated to give phenyl3-(morpholinomethyl)-5-(trifluoromethyl)phenylcarbamate. ¹H NMR(DMSO-d₆) δ 10.58(s, 1H), 7.8 (d, 2H), 7.4 (m, 2H), 7.3 (m, 4H), 3.6 (m,6H), 2.37 (s, 4H).

Example 151B: The procedure described in Example 138B was used to reactphenyl 3-(morpholinomethyl)-5-(trifluoromethyl)phenylcarbamate (140 mg,0.37 mmol) with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example113A (78 mg, 0.25 mmol). To this solution was added diisopropylethylamine (64 μL, 0.37 mmol) and DMAP (3.0 mg, 0.03 mmol). The reaction wasconcentrated to dryness and triturated with methanol to give1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)urea(47 mg, 32% yield). ¹H NMR (DMSO-d₆) δ 9.15 (s, 1H), 8.97 (s, 1H), 8.57(s, 1H), 7.92 (s, 1H), 7.60 (m, 3H), 7.40 (m, 2H), 7.28 (m, 2H), 6.96(m, 1H), 4.00 (s, 6H), 3.51 (s, 4H), 3.38 (s, 2H), 2.35 (s, 4H). LCMS(ESI) m/z 584 (M+H)⁺.

Example 152 Preparation of 1-(3-(1,1-difluoroethyl)isoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 152A Step 1: In a round bottomed flask flushed with argon, asuspension of sodium hydride 60% in mineral oil (1.30 g, 34 mmoles) wasrinsed twice with hexane, and suspended in 20 mL of dry THF. Thesolution was heated to 75° C., and ethyl difluoropropionate (3.00 g, 22mmoles) and acetonitrile (1.78 mL) in 5 ml of dry THF was added dropwiseover 30 minutes. The temperature of the reaction was lowered to 65° C.and stirred overnight. The mixture was then concentrated to an oil andpartitioned between water and ether, and extracted twice to remove anymineral oil and other impurities. The aqueous layer was acidified topH=1 with 10% HCl, and the solution extracted twice. These extracts weredried over magnesium sulfate, filtered and concentrated to a crude oil.The crude product was purified using silica gel chromatography using agradient of 10-40% ethyl acetate/hexane to afford4,4-difluoro-3-oxo-pentanenitrile ¹H (300 MHz, CDCl₃) δ 3.95 (s, 2H),1.86 (m, 3H).

Example 152A Step 2: The above ketonitrile (100 mg, 0.75 mmoles) wasdissolved in 2 mL of ethanol, to this solution an aqueous solution ofsodium hydroxide (33 mg, 0.82 mmoles) in 2 ml of water was added andstirred for 10 minutes. To this solution hydroxylamine sulfate (135 mg,0.82 mmoles) was added in a single portion and stirred at roomtemperature for 15 minutes. The reaction was then heated to 80 Covernight. The solution was concentrated to one half the volume, dilutedwith water and extracted twice with ether. The ether extracts were driedover magnesium sulfate, filtered, and concentrated to give3-(1,1-difluoro-ethyl)-isoxazol-5-ylamine (100 mg). ¹H NMR (300 MHz,CDCl₃) δ 5.3 (s, 1H), 4.7 (s, 2H), 2.0 (m, 3H); LCMS (ESI) m/z 149(M+H)⁺.

Example 152A Step 3: 3-(1,1-Difluoro-ethyl)-isoxazol-5-ylamine (100 mg,0.68 mmoles) from the previous step was dissolved in 6 mL of dry THF. Tothis solution was added potassium carbonate (122 mg, 0.88 mmoles) andphenyl chloroformate (138 mg, 0.88 mmoles) and the reaction stirredovernight at room temperature. The reaction was filtered andconcentrated to a yellow oil, and purified using silica gelchromatography with and ethyl acetate/hexane gradient 0-20% over 70minutes to give phenyl 3-(1,1-difluoroethyl)isoxazol-5-ylcarbamate (141mg) as an oil. ¹H NMR (300 MHz, CDCl₃) δ 8.1 (s, 1H), 7.4-7.1 (m, 5H),6.9 (m, 1H), 6.4 (s, 1H), 4.9 (s, 1H), 2.0 (m, 3H).

Example 152B. The carbamate from the previous step (141 mg, 0.52 mmol)was reacted as described in Example 138B with the3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (156 mg,0.52 mmol). To this solution was added diisopropylethyl amine (136 μL,0.78 mmol) and DMAP (5.0 mg, 0.04 mmol). The reaction was concentratedto dryness and partitioned between water and dichloromethane, andextracted twice. The combined extracts were washed with brine, driedover magnesium sulfate, filtered and concentrated. The oil was purifiedby reversed phase HPLC using a phenyl hexyl column eluting with agradient of 40-70% acetonitrile/water over 60 minutes. The main peak wascollected, concentrated, and lyophilized to afford the title compound(66 mg, 27% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 10.70 (s, 1H), 9.15 (s,1H), 8.58 (s, 1H), 7.56 (s, 1H), 7.45 (m, 2H), 7.40 (m, 1H), 7.00 (m,1H), 6.25 (s, 1H), 3.99 (s, 3H), 3.80 (s, 6H), 2.0 (m, 3H). LCMS (ESI)m/z 472 (M+H)

Example 153 Preparation of1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 153A: Using the procedure described in Example 161C,3-tert-butyl-1-phenyl-1H-pyrazol-5-amine (2.00 g, 9.3 mmol) was reactedwith phenyl chloroformate (1.6 g, 10.2 mmol) and K₂CO₃ (1.7 g, 12.1mmol) in THF (20 mL), which was purified by silica gel chromatography(0-50% EtOAc/hexane) to afford phenyl3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate as solid (1.3 g, 42%). ¹HNMR (300 MHz, DMSO-d₆) δ 10.0 (s, 1H), 7.55 (m, 4H), 7.40 (m, 3H),7.08-7.23 (m, 3H), 6.37 (s, 1H), 1.3 (s, 9H); LC-MS (ESI) m/z 336(M+H)⁺.

Example 153B. The resulting carbamate (151 mg, 0.45 mmol) was reacted asdescribed in Example 138B with3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg,0.30 mmol) using diisopropylethyl amine (80 μL/0.45 mmol) and DMAP (4mg, 0.03 mmol). After heating for 2 hours at 50° C. the reaction wasconcentrated to dryness. The resulting solid purified by silica gelchromatography (eluting with 0-85% ethyl acetate/hexane) to afford thetitle compound (68 mg, 42% yield). ¹H NMR (DMSO-d₆) δ 9.13 (s, 1H), 8.55(s, 1H), 8.47 (s, 1H), 7.55 (m, 6H), 7.40 (m, 3H), 7.15 (s, 1H), 6.95(m, 1H), 6.36 (s, 1H), 4.00 (s, 6H), 1.25 (s, 9H). LCMS (ESI) m/z 539(M+H).

Example 154 Preparation of1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

According to the procedure described in Example 138B, phenyl3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (151 mg, 0.45 mmol) fromExample 153A was reacted with3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (89 mg,0.30 mmol). To this solution was added diisopropylethyl amine (80 μL,0.45 mmol) and DMAP (4 mg, 0.03 mmol). After heating for 2 hours at 50°C., the reaction was concentrated to dryness. The resulting solid wastriturated with 1:1 dichloromethane/hexane and the solid removed byfiltration to afford the title compound (83 mg, 50% yield). ¹H NMR (300MHz, DMSO-d₆) δ 9.24 (s, 1H), 8.68 (s, 1H), 8.47 (s, 1H), 7.55 (m, 4H),7.40 (m, 5H), 7.20 (s, 1H), 6.95 (m, 1H), 6.36 (s, 1H), 3.98 (s, 6H),1.25 (s, 9H); LCMS (ESI) m/z 555 (M+H)⁺.

Example 155 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(1-(trifluoromethyl)cyclobutyl)isoxazol-5-yl)urea

Example 155A Step 1: Methyl 1-(trifluoromethyl)cyclobutanecarboxylate (2g, 11 mmol) was reacted according to the procedure described in Example122A Step 1, to afford3-oxo-3-(1-(trifluoromethyl)cyclobutyl)propanenitrile as a yellow oil(1.68 g, 80%) which was used in the next step without furtherpurification. ¹H NMR (300 MHz, CDCl₃) δ 3.70 (s, 2H), 2.39-2.65 (m, 4H),1.95-2.15 (m, 2H).

Example 155A Step 2:3-Oxo-3-(1(trifluoromethyl)cyclobutyl)propanenitrile (500 mg, 2.6 mmol)was reacted according to the procedure described in Example 122A Step 2to afford 3-(1-(trifluoromethyl)cyclobutyl)isoxazol-5-amine as acolorless solid (210 mg, 39%). ¹H NMR (300 MHz, CDCl₃) δ 5.04 (s, 1H),4.55 (brs, 2H), 2.40-2.60 (m, 4H), 1.90-2.10 (m, 2H).

Example 155A Step 3: 3-(1-(Trifluoromethyl)cyclobutyl)isoxazol-5-amine(210 mg, 1.0 mmol) was reacted according to the procedure described inExample 12A Step 3, to afford phenyl3-(1-(trifluoromethyl)cyclobutyl)isoxazol-5-ylcarbamate as a colorlesssolid (320 mg, 98%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.17 (brs, 1H),7.10-7.54 (m, 5H), 6.08 (s, 1H), 2.50-2.70 (m, 4H), 1.90-2.10 (m, 2H);LC-MS (ESI) m/z 327 (M+H)⁺.

Example 155B. The resulting carbamate intermediate (147 mg, 0.45 mmol)from the previous step was reacted as described in Example 138B with3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg,0.30 mmol) and diisopropylethyl amine (80 μL, 0.45 mmol) and DMAP (4 mg,0.03 mmol). After heating for 2 hours the reaction was concentrated todryness. The resulting solid was purified by silica gel chromatographyeluting with a 0-100% ethyl acetate/hexane gradient over 60 minutes. Theappropriate fractions were concentrated to a solid weighing 74 mg. ¹HNMR (300 MHz, DMSO-d₆) δ 10.48 (s, 1H), 9.11 (s, 1H), 8.56 (s, 1H), 7.79(s, 1H), 7.57 (m, 2H), 7.40 (m, 2H), 7.39 (s, 1H), 7.01 (m, 1H), 6.08(s, 1H), 3.99 (s, 6H), 2.58 (m, 4H), 2.03 (s, 2H). LCMS (ESI) m/z 530(M+H)⁺.

Example 156 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(1-(trifluoromethyl)cyclobutyl)isoxazol-5-yl)urea

The procedure for Example 138B was used to reactphenyl-3-(1-(trifluoromethyl)cyclobutyl)isoxazol-5-y carbamate (147 mg,0.45 mmol) with 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example115B (94 mg, 0.30 mmol). To this solution was added diisopropylethylamine (80 μL, 0.45 mmol) and DMAP (4 mg, 0.03 mmol). After heating for 2hours the reaction was concentrated to dryness. The resulting solid waspurified by silica gel chromatography (eluting with a 0-100% ethylacetate/hexane gradient) to afford the title compound (42 mg). ¹H NMR(300 MHz, DMSO-d₆) δ 10.49 (s, 1H), 9.13 (s, 1H), 8.69 (s, 1H), 7.84 (s,1H), 7.7-7.2 (m, 5H), 6.08 (s, 1H), 3.99 (s, 6H), 2.58 (m, 4H), 2.03 (s,2H); LCMS (ESI) m/z 546 (M+H)⁺.

Example 157 Preparation of1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

Example 157A: According to the procedure described in Example 161C,3-tert-butyl-1-methyl-1H-pyrazol-5-amine (1.0 g, 6.5 mmol), and K₂CO₃(1.17 g, 8.5 mmol) in THF (15 mL) were reacted with phenyl chloroformate(1.12 g, 7.2 mmol). The crude product was purified by silica gelchromatography with 0-50% EtOAc/hexane gradient to afford phenyl3-tert-butyl-1-methyl-1H-pyrazol-5-ylcarbamate as solid (0.53 g, 31%).¹H NMR (300 MHz, DMSO-d₆) δ 10.2 (s, 1H), 7.43 (m, 2H), 7.25 (m, 3H),6.06 (s, 1H), 3.66 (s, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 274 (M+H)⁺.

Example 157B: The procedure for Example 138B was used to react phenyl3-tert-butyl-1-methyl-1H-pyrazol-5-ylcarbamate (123 mg, 0.45 mmol) with3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg,0.30 mmol). To this solution was added diisopropylethyl amine (80 μL,0.45 mmol) and DMAP (4 mg, 0.03 mmol). After heating for 2 hours thereaction was concentrated to dryness. The resulting solid was purifiedby silica gel chromatography eluting with an ethyl acetate/hexanegradient 0-100% over 60 minutes. The appropriate fractions wereconcentrated to a solid weighing 102 mg. ¹H NMR (300 MHz, DMSO-d₆) δ9.15 (s, 1H), 8.75 (s, 1H), 8.56 (s, 1H), 7.85 (s, 1H), 7.65-7.15 (m,5H), 6.08 (s, 1H), 4.00 (s, 6H), 3.65 (s, 3H), 1.25 (s, 9H). LCMS (ESI)m/z 493 (M+H)⁺.

Example 158 Preparation of1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 158A. According to the procedure described in Example 161C, to asuspension of 3-tert-butyl-1-methyl-1H-pyrazol-5-amine (1.0 g, 6.5 mmol)and K₂CO₃ (1.17 g, 8.5 mmol) in THF (15 mL) was added phenylchloroformate (1.12 g, 7.2 mmol). The crude product was purified bysilica gel chromatography with 0-50% EtOAc/hexane as eluants to affordphenyl 3-tert-butyl-1-methyl-1H-pyrazol-5-ylcarbamate as solid (0.53 g,31%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.2 (s, 1H), 7.43 (m, 2H), 7.25 (m,3H), 6.06 (s, 1H), 3.66 (s, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 274(M+H)⁺.

Example 158B. The resulting carbamate (123 mg, 0.45 mmol) was reacted asdescribed in Example 138B with the intermediate amine (89 mg, 0.30 mmol)using diisopropylethyl amine (80 μL, 0.45 mmol) and DMAP (4 mg, 0.03mmol). After heating for 2 hours at 50° C., the reaction wasconcentrated to dryness. The resulting solid was purified by silica gelchromatography eluting with a gradient of 0-100% ethyl acetate/hexane toafford the title compound (102 mg, 71% yield). ¹H NMR (300 MHz, DMSO-d₆)δ 9.20 (s, 1H), 8.56 (s, 1H), 7.53 (m, 2H), 7.50 (m, 2H), 7.30 (m, 1H),6.95 (m, 1H), 6.08 (s, 1H), 3.99 (s, 6H), 3.54 (s, 3H), 1.25 (s, 9H).LC-MS (ESI) m/z 477 (M+H)⁺.

Example 159 Preparation of1-[3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-yloxy]phenyl)urea

Example 159A Step 1: To a solution of5-fluoro-4-(fluoromethyl)-4-methyl-3-oxopentanenitrile (1.00 g, 6.2mmol) and NaOH (0.272 g, 6.8 mmol) in EtOH (5 mL) and water (5 mL) atroom temperature was added a solution of hydroxylamine sulfate (1.12 g,6.8 mmol) in water (5 mL). To the mixture was added additional NaOHuntil the pH was about 8. After heating at 100° C. for 2 hours, it wasquenched with water and extracted with CH₂Cl₂. Extracts were washed withwater, dried over MgSO₄, and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluted with gradientof 0-50% EtOAc/hexane to afford3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-amine as a solid (0.191g, 17%). ¹H NMR (300 MHz, CDCl₃) δ 5.16 (s, 1H), 4.63 (q, 2H), 4.5 (qand br, 4H), 1.37 (s, 3H); LC-MS (ESI) m/z 177 (M+H)⁺.

Example 159A Step 2: Using the procedure described in Example 161C,3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-amine (0.19 g, 1.08 mmol)was reacted with phenyl chloroformate (0.235 g, 1.5 mmol) in thepresence of K₂CO₃ (0.276 g, 2 mmol) in THF (10 mL), and purified bysilica gel chromatography with 10-25% EtOAc/hexane as eluants to affordphenyl 3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate assolid (0.319 g, 100%). ¹H NMR (300 MHz, CDCl₃) δ 7.83 (s, 1H), 7.17-7.45(m, 5H), 6.23 (s, 1H), 4.69 (dq, 2H), 4.50 (dq, 2H), 1.40 (s, 3H); LC-MS(ESI) m/z 297 (M+H)⁺.

Example 159B: A mixture of phenyl3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate (0.158 g, 0.5mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A(0.119 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6mL) was heated at 50° C. for 5 hours. It was quenched with saturatedNaHCO₃ and extracted with CH₂Cl₂. Extracts were dried over MgSO₄ andconcentrated under reduced pressure. It was purified by silica gelchromatography with 40-95% EtOAc/hexane as eluants to afford1-[3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-yloxy]phenyl)ureaas solid (0.115 g, 58%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.33 (s, 1H), 9.00(s, 1H), 8.55 (s, 1H), 7.56 (m, 3H), 7.39 (s, 1H), 7.27 (s and d, 2H),6.24 (s, 1H), 4.73 (m, 2H), 4.56 (m, 2H), 3.99 (s, 3H), 3.98 (s, 3H),1.30 (s, 3H); LC-MS (ESI) m/z 500 (M+H)⁺.

Example 160 Preparation of1-[3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-ylthio]phenyl)urea

Using the procedure described in Example 159B, a mixture of phenyl3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate described inExample 159A (0.158 g, 0.5 mmol),3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g,0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) wereheated at 50° C. for 5 hours, to afford1-[3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]ureaas solid (0.114 g, 55%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.38 (s, 1H), 9.10(s, 1H), 8.70 (s, 1H), 7.85 (s, 1H), 7.56 (d, 1H), 7.46 (t, 1H), 7.34(m, 3H), 6.22 (s, 1H), 4.70 (m, 2H), 4.55 (m, 2H), 3.99 (s, 6H), 1.28(s, 3H); LC-MS (ESI) m/z 516 (M+H)⁺.

Example 1611-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea

Example 161A Step 1: To a solution of triethyl orthoacetate (8.11 g, 50mmol) and pyridine (9.10 g, 115 mmol) in CH₂Cl₂ (50 mL) at 0° C. wasdropped 2,2,2-trifluoroacetic anhydride (21.00 g, 100 mmol). Afterstirred at room temperature overnight, it was quenched with coldsaturated NaHCO₃ solution and washed with water. The organic layer wasdried over MgSO₄, concentrated under reduced pressure, and dried undervacuum to afford 4,4-diethoxy-1,1,1-trifluorobut-3-en-2-one as an oil(10.116 g, 95%). ¹H NMR (300 MHz, CDCl₃) δ 4.94 (s, 1H), 4.37 (q, 2H),4.15 (q, 2H), 1.46 (t, 3H), 1.42 (t, 3H); LC-MS (ESI) m/z 213 (M+H)⁺.

Example 161A Step 2: To a solution of4,4-diethoxy-1,1,1-trifluorobut-3-en-2-one (7.94 g, 37.4 mmol) in MeCN(30 mL) at room temperature was dropped 28% solution of NH₄OH in water(7 mL). It was stirred at room temperature overnight. After solvent wasremoved under reduced pressure, to it was added CH₂Cl₂ and washed withwater. The organic layer was dried over MgSO₄ and concentrated underreduced pressure to afford(E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one as solid (6.371 g,93%). ¹H NMR (300 MHz, CDCl₃) δ 9.79 (br, 1H), 5.66 br, 1H), 5.13 (s,1H), 4.15 (q, 2H), 1.38 (t, 3H); LC-MS (ESI) m/z 184 (M+H)⁺.

Example 161A Step 3: A mixture of(E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2.93 g, 16 mmol) andphenylhydrazine (1.947 g, 18 mmol) in EtOH (15 mL) was heated at 95° C.for 8 hours. The reaction was quenched with water and extracted withCH₂Cl₂. Extracts were dried over MgSO₄ and concentrated under reducedpressure. The crude product was purified by silica gel chromatographywith 5-25% EtOAc/hexane as eluants to afford1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine as a yellow solid (2.23g, 66%). ¹H NMR (300 MHz, CDCl₃) δ 7.51 (m, 5H), 5.87 (s, 1H), 3.93 (br,2H); LC-MS (ESI) m/z 228 (M+H)⁺.

Alternative Preparation of1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine

Step 161B Step 1: To a suspension of NaH (2.88 g, 120 mmol) in THF (70mL) at 80° C. was dropped a solution of methyl 2,2,2-trifluoroacetate(10.244 g, 80 mmol) in MeCN (5.377 g, 130 mmol) over 40 minutes. Themixture was heated at 70° C. for 2 hours and stirred at room temperatureovernight. The reaction was quenched with water, acidified with 10% HClsolution to pH 1, and extracted with CH₂Cl₂. Extracts were dried overMgSO₄, concentrated under reduced pressure, and dried under vacuum toafford 4,4,4-trifluoro-3-oxobutanenitrile as an oil (9.084 g, 83%). ¹HNMR (300 MHz, CDCl₃) δ 2.93 (s, 2H).

Example 161B Step 2: A mixture of 4,4,4-trifluoro-3-oxobutanenitrile(2.056 g, 15 mmol) and phenylhydrazine hydrochloride (2.169 g, 15 mmol)in EtOH was heated at 90° C. for 8 hours. The reaction was quenched withwater, basified with saturated NaHCO₃ solution, and extracted withCH₂Cl₂. Extracts were dried over MgSO₄, concentrated under reducedpressure, and dried under vacuum to afford1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine as yellow solid (3.089g, 91%). ¹H NMR (300 MHz, CDCl₃) δ 7.54 (m, 5H), 5.85 (s, 1H), 3.95 (br,2H); LC-MS (ESI) m/z 228 (M+H)⁺.

Example 161C: To a suspension of1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (1.136 g, 5 mmol) andK₂CO₃ (1.035 g, 7.5 mmol) in THF (20 mL) was dropped a solution ofphenyl chloroformate (0.939 g, 6 mmol) in THF (10 mL). After stirred atroom temperature overnight, the mixture was quenched with water andextracted with CH₂Cl₂. Extracts were dried over MgSO₄, concentratedunder reduced pressure, and dried under vacuum to afford phenyl1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate as solid (1.714 g,99%). ¹H NMR (300 MHz, CDCl₃) δ 7.55 (m, 5H), 7.39 (m, 2H), 7.28 (m,2H), 7.14 (m, 2H), 6.86 (m, 1H); LC-MS (ESI) m/z 348 (M+H)⁺.

Example 161D. The title compound was prepared as described in Example159B, using phenyl 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamatefrom the previous step (0.139 g, 0.4 mmol),3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g,0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50°C. for 6 hours, to afford1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]ureaas solid (0.116 g, 53%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 8.80(s, 1H), 8.55 (s, 1H), 7.54-7.62 (m, 7H), 7.39 (m, 2H), 7.19 (d, 1H),6.96 (d, 1H), 6.86 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H); LC-MS (ESI) m/z551 (M+H)⁺.

Example 162 Preparation of1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]urea

Example 162A Step 1: To a mixture of hydroxylamine sulfate (0.59 g, 3.6mmol) and NaHCO₃ (0.700 g, 8.3 mmol) in MeOH (1 mL) and water (10 mL)was added 5-fluoro-4-(fluoromethyl)-4-methyl-3-oxopentanenitrile (0.483g, 3 mmol). After heated at 60° C. for 8 hours, to it was added 10% HCluntil pH 1. It was heated at 60° C. for 3 hours, basified with saturatedNaHCO₃, and extracted with CH₂Cl₂. Extracts were dried over MgSO₄ andconcentrated under reduced pressure to afford5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-amine as needles (0.289g, 55%). ¹H NMR (300 MHz, CDCl₃) δ 5.76 (s, 1H), 4.59 (q, 2H), 4.50 (qand br, 4H), 1.37 (s, 3H); LC-MS (ESI) m/z 177 (M+H)⁺.

Example 162A Step 2: Using the procedure described in Example 161C,using 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-amine (0.287 g, 1.6mmol), phenyl chloroformate (0.313 g, 2 mmol) were reacted in thepresence of K₂CO₃ (0.345 g, 2.5 mmol) in THF (15 mL), and purified bysilica gel chromatography (using 5-25% EtOAc/hexane as eluants) toafford phenyl 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamateas a solid (0.358 g, 76%). ¹H NMR (300 MHz, CDCl₃) δ 8.17 (br, 1H), 7.42(m, 2H), 7.26 (m, 1H), 7.20 (m, 2H), 6.81 (s, 1H), 4.67 (q, 2H), 4.51(q, 2H), 1.42 (s, 3H); LC-MS (ESI) m/z 297 (M+H)⁺.

Example 162B: A mixture of phenyl5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate from theprevious step (0.089 g, 0.3 mmol),3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.089 g,0.3 mmol), and 4-(dimethylamino)pyridine (0.03 g) in THF (6 mL) wasstirred at room temperature overnight. The reaction was quenched withwater and extracted with CH₂Cl₂. Extracts were dried over MgSO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography (eluting with 70-95% EtOAc/hexane) to afford1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]ureaas solid (0.055 g, 31%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.70 (s, 1H), 9.02(s, 1H), 8.57 (s, 1H), 7.57 (m, 2H), 7.40 (m, 2H), 7.27 (d, 1H), 6.98(d, 1H), 6.77 (s, 1H), 4.71 (s, 2H), 4.56 (s, 2H), 4.00 (s, 3H), 3.98(s, 3H), 1.28 (s, 3H); LC-MS (ESI) m/z 500 (M+H)⁺.

Example 163 Preparation of1-(3-cyclopentylisoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 163A: Using the procedure described in Example 113B butsubstituting 3-cyclopentylisoxazol-5-amine (675 mg, 4.44 mmol) for the5-phenylisoxazole-3-amine, phenyl 3-cyclopentylisoxazol-5-ylcarbamate(528 mg, 50%) was afforded as a white solid. ¹H NMR (300 MHz, CDCl₃) δ8.21 (bs, 1H), 7.44-7.39 (m, 2H), 7.30-7.26 (m, 1H), 7.21 (d, 2H), 6.06(s, 1H), 3.17-3.07 (m, 1H), 2.06-1.99 (m, 2H), 1.76-1.63 (m, 6H); LC-MS(ESI) m/z 273 (M+H)⁺.

Example 163B: Using the procedure described in Example 113C,3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (104 mg,0.35 mmol) and the carbamate from the previous step (124 mg, 0.45 mmol)were reacted in the presence of N,N-diisopropylethylamine (73 μl, 0.42mmol) to give1-(3-cyclopentylisoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(75.22 mg, 45%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.18 (s,1H), 9.05 (s, 1H), 8.56 (s, 1H) 7.57 (s, 2H), 7.56-7.39 (t, 2H) 7.29 (d,1H), 6.98 (d, 1H), 5.95 (s, 1H), 4.00 (s, 6H), 3.04-3.01 (m, 1H),1.99-1.93 (m, 2H), 1.69-1.61 (m, 6H)); LC-MS (ESI) m/z 476 (M+H)⁺.

Example 164 Preparation of1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea

Example 164A Step 1: Using the procedure described in Example 161A Step3, (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2.34 g, 12.78mmol) and methylhydrazine (0.645 g, 14 mmol) were reacted in EtOH (10mL) at 95° C. for 8 hours, and purified by silica gel chromatographywith 30-40% EtOAc/hexane as eluants to afford1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-amine as solid (1.733 g,68.3%). MP: 100-101° C.; ¹H NMR (300 MHz, CDCl₃) δ 5.80 (s, 1H), 3.71(s, 3H), 3.62 (br, 2H); LC-MS (ESI) m/z 166 (M+H)⁺.

Example 164B: Using the procedure described in Example 161C,1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (1.70 g, 10.3 mmol) andphenyl chloroformate (1.88 g, 12 mmol) were reacted to afford phenyl1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate as solid (0.760 g,26%). LC-MS (ESI) m/z 286 (M+H)⁺.

Example 164C: Using the procedure described in Example 159B, phenyl1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate from the previousstep (0.114 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)anilinefrom Example 113A (0.119 g, 0.4 mmol), and N,N-diisopropylethylamine(0.3 mL) in THF (6 mL) were heated at 50° C. for 3 hours, to afford1-[3-(6,7-Dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]ureaas solid (0.047 g, 24%). ¹H NMR (300 MHz, CDCl₃) δ 9.6 (br, 1H), 8.64(s, 1H), 7.63 (m, 1H), 7.57 (s, 1H), 7.43 (t, 1H), 7.33 (m, 2H), 7.01(d, 1H), 6.94 (s, 1H), 6.26 (s, 1H), 4.08 (s, 6H), 3.93 (s, 3H); LC-MS(ESI) m/z 489 (M+H)⁺.

Example 165 Preparation of1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]urea

Example 165A Step 1: Using the procedure described in Example 161A Step3, (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (1.83 g, 10 mmol)and methylhydrazine sulfate (1.586 g, 11 mmol) were reacted and thecrude product purified by silica gel chromatography (with 0-10%EtOAc/CH₂Cl₂ as eluants) to afford1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine as solid (0.381 g, 23%).¹H NMR (300 MHz, CDCl₃) δ 5.94 (s, 1H), 3.78 (s, 3H), 3.67 (br, 2H);LC-MS (ESI) m/z 166 (M+H)⁺.

Example 165A Step 2: Using the procedure described in Example 161C,1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (0.38 g, 2.3 mmol) andphenyl chloroformate (0.438 g, 2.8 mmol) were reacted in the presence ofK₂CO₃ (0.415 g, 3 mmol) in THF (10 mL), to afford phenyl1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate as solid (0.465 g,71%). ¹H NMR (300 MHz, CDCl₃) δ 8.05 (s, 1H), 7.17-7.45 (m, 5H), 6.93(s, 1H), 3.91 (s, 3H); LC-MS (ESI) m/z 286 (M+H)⁺.

Example 165B: Using the procedure described in Example 159B, phenyl1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate from the previousstep (0.114 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)anilinefrom Example 113A (0.119 g, 0.4 mmol), and N,N-diisopropylethylamine(0.5 mL) in THF (6 mL) were heated at 50° C. for 3 hours, to afford1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]ureaas solid (0.041 g, 21%). ¹H NMR (300 MHz, CDCl₃) δ 9.6 (br, 1H), 8.65(s, 1H), 7.63 (m, 1H), 7.61 (s, 1H), 7.43 (t, 1H), 7.33 (m, 2H), 7.02(dd, 1H), 6.92 (s, 1H), 6.25 (s, 1H), 4.08 (s, 6H), 3.93 (s, 3H); LC-MS(ESI) m/z 489 (M+H)⁺.

Example 166 Preparation of ethyl2-(3-tert-butyl-5-{3-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]ureido}-1H-pyrazol-1-yl)acetate

Example 166A Step 1: A mixture of ethyl 2-hydrazinylacetatehydrochloride (0.309 g, 2 mmol), NaHC O₃ (0.185 g, 2.2 mmol), and4,4-dimethyl-3-oxopentanenitrile (0.250 g, 2 mmol) in EtOH (10 mL) washeated at 60° C. overnight. The reaction was quenched with water andextracted with CH₂Cl₂. Extracts were dried over MgSO₄ and concentratedunder reduced pressure to afford ethyl2-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)acetate as solid (0.369 g, 82%).¹H NMR (300 MHz, CDCl₃) δ 5.50 (s, 1H), 4.75 (s, 2H), 4.23 (q, 2H), 3.57(br, 2H), 1.29 (t, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 226 (M+H)⁺.

Example 166A Step 2: In the manner described in Example 161C, usingethyl 2-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)acetate (1.68 g, 7.46mmol), phenyl chloroformate (1.284 g, 8.2 mmol), and K₂CO₃ (1.52 g, 11mmol) in THF (20 mL), which was purified by silica gel chromatographywith 0-40% EtOAc/hexane as eluants to afford ethyl2-[3-tert-butyl-5-(phenoxycarbonylamino)-1H-pyrazol-1-yl]acetate assolid (1.115 g, 43%). ¹H NMR (300 MHz, CDCl₃) δ 7.37-7.43 (m, 2H),7.25-7.27 (m, 2H), 7.21 (m, 2H), 6.25 (s, 1H), 4.88 (s, 2H), 4.28 (q,2H), 1.33 (t, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 346 (M+H)⁺.

Example 166B: In the manner described in Example 159B, ethyl2-[3-tert-butyl-5-(phenoxycarbonylamino)-1H-pyrazol-1-yl]acetate fromthe previous step (0.138 g, 0.4 mmol) was reacted with3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g,0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) at 50°C. for 7 hours, to afford ethyl2-(3-tert-butyl-5-{3-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]ureido}-1H-pyrazol-1-yl)acetateas solid (0.145 g, 66%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.59(s, 1H), 8.56 (s, 1H), 7.59 (m, 1H), 7.56 (s, 1H), 7.39 (m, 2H), 7.22(d, 1H), 6.94 (d, 1H), 6.11 (s, 1H), 4.85 (s, 2H), 4.16 (q, 2H), 3.99(s, 6H), 1.19 (t and s, 12H); LC-MS (ESI) m/z 549 (M+H)⁺.

Example 167 Preparation of1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]urea

Example 167A Step 1: To a suspension of3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid (10.06 g, 75 mmol) inMeOH was dropped 2.0 M solution of (trimethylsilyl)diazomethane indiethyl ether and stirred at room temperature overnight. After solventwas concentrated under reduced pressure, the reaction was quenched withsaturated NaHCO₃ solution and extracted with CH₂Cl₂. Extracts were driedover MgSO₄ and concentrated under reduced pressure to afford methyl3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate as an oil (3.79 g, 34%).¹H NMR (300 MHz, CDCl₃) δ 3.81 (d, 2H), 3.67 (s, 3H), 3.60 (d, 2H), 2.89(br, 2H), 0.96 (s, 3H).

Example 167A Step 2: To a solution of methyl3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate (13.04 g, 88 mmol) and2,6-lutidine (26.79 g, 250 mmol) in CH₂Cl₂ at −78° C. under argon wasdropped neat trifluoroacetic anhydride (50.00 g, 177 mmol). It wasstirred for 2 hours, at which time the temperature was raised to roomtemperature and the mixture was stirred for 2 more hours at roomtemperature. The reaction was quenched with CH₂Cl₂ (200 mL), washed with3% HCl solution (200 mL), dried over MgSO₄, and concentrated to drynessto provide an oil.

The oil was dissolved in THF (50 mL) and cooled with ice bath. To it wasadded 1.0 M solution of tetrabutylammonium fluoride in THF (200 mL). Thesolution was stirred at room temperature overnight. After solvent wasconcentrated under reduced pressure, CH₂Cl₂ (400 mL) was added, and thesolution was washed with brine twice (200 mL×2), dried over MgSO₄, andconcentrated under reduced pressure. It was distilled under reducedpressure and the fraction was collected at about 60° C. to afford methyl3-fluoro-2-(fluoromethyl)-2-methylpropanoate as an oil (2.89 g, 22%). ¹HNMR (300 MHz, CDCl₃) δ 4.33-4.66 (m, 4H), 3.67 (s, 3H), 1.14 (s, 3H).

Example 167A Step 3: According to the procedure described in Example161B Step 1, methyl 3-fluoro-2-(fluoromethyl)-2-methylpropanoate (5.21g, 34.2 mmol), NaH (1.248 g, 52 mmol), and MeCN (2.791 g, 68 mmol) inTHF (40 mL) were heated at 70° C. overnight, to afford5-fluoro-4-(fluoromethyl)-4-methyl-3-oxopentanenitrile as oil (4.412 g,80%). ¹H NMR (300 MHz, CDCl₃) δ 4.67 (m, 2H), 4.52 (m, 2H), 3.80 (s,2H), 1.27 (s, 3H).

Example 167A Step 4: According to the procedure described in Example161B Step 2,5-fluoro-4-(fluoromethyl)-4-methyl-3-oxopentanenitrile (0.81g, 5 mmol) and phenylhydrazine hydrochloride (0.868 g, 14 mmol) in EtOHwere heated at 95° C. for 2 hours, to afford3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-amine assolid (0.75 g, 52%). LC-MS (ESI) m/z 252 (M+H)⁺.

Example 167B: According to the procedure described in Example 161C, to asolution of3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-amine (0.75g, 2.98 mmol) in THF (25 mL) and K₂CO₃ (1.037 g, 7.5 mmol), was addedphenyl chloroformate (0.548 g, 3.5 mmol). The crude product was purifiedby silica gel chromatography (with 10-25% EtOAc/hexane as eluants) toafford phenyl3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamateas solid (1.143 g, 100%). ¹H NMR (300 MHz, CDCl₃) δ 7.5 (m, 3H), 7.4 (m,4H), 7.2 (m, 4H), 6.6 (s, 1H), 4.75 (q, 2H), 4.55 (q, 2H), 1.4 (s, 3H);LC-MS (ESI) m/z 372 (M+H)⁺.

Example 167C: Using the procedure described in Example 159B, phenyl3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamatefrom the previous step (0.186 g, 0.5 mmol) was reacted with3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g,0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50°C. for 6 hours, to afford1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]ureaas solid (0.037 g, 16%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.54(s, 2H), 7.56 (m, 7H), 7.50 (d, 1H), 7.38 (s, 1H), 7.22 (m, 2H), 6.54(s, 1H), 4.73 (m, 2H), 4.58 (m, 2H), 3.99 (s, 3H), 3.97 (s, 3H), 1.33(s, 3H); LC-MS (ESI) m/z 575 (M+H)⁺.

Example 168 Preparation of1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]urea

Example 168A: Using the procedure described in Example 161B Step 2,using 4-fluoro-4-methyl-3-oxopentanenitrile (0.77 g, 6 mmol) andphenylhydrazine hydrochloride (0.954 g, 6.6 mmol) in EtOH at 95° C. for3 hours, which was purified by silica gel chromatography with 10-35%EtOAc/hexane to afford3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-amine as solid (0.315 g,24%). ¹H NMR (300 MHz, CDCl₃) δ 7.54 (m, 2H), 7.43 (m, 2H), 7.27 (m,1H), 5.60 (s, 1H), 3.83 (br, 2H), 3.35 (q, 2H), 1.63 (s, 6H), 1.15 (t,3H); LC-MS (ESI) m/z 246 (M+H)⁺.

Example 168B: Using the procedure described in Example 161C,3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-amine (0.429 g, 1.75 mmol)and phenyl chloroformate (0.329 g, 2.1 mmol) were reacted in thepresence of K₂CO₃ (0.415 g, 3 mmol) in THF (15 mL), and purified bysilica gel chromatography with 15-35% EtOAc/hexane as eluants to affordphenyl 3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate assolid (0.594 g, 93%). ¹H NMR (300 MHz, CDCl₃) δ 7.53 (m, 5H), 7.41-7.48(m, 4H), 7.14-7.38 (m, 2H), 6.6 (s, 1H), 3.37 (q, 2H), 1.59 (s, 6H),1.14 (t, 3H); LC-MS (ESI) m/z 320 (M−OEt)⁺.

Example 168C: Using the procedure described in Example 159B, phenyl3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate (0.115 g, 0.33mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A(0.098 g, 0.33 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6mL) were heated at 50° C. for 5 hours, to afford1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]ureaas solid (0.113 g, 60%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (br, 1H), 8.55(s, 1H), 8.54 (s, 1H), 7.54 (m, 6H), 7.39 (m, 3H), 7.18 (d, 1H), 6.93(d, 1H), 6.41 (s, 1H), 3.77 (s, 3H), 3.98 (s, 3H), 3.25 (q, 2H), 1.45(s, 6H), 1.03 (t, 3H); LC-MS (ESI) m/z 523 (M−OEt)⁺.

Example 169 Preparation of1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]urea

Example 169A Step 1. To a solution of NaOEt (10.893 g, 160 mmol) in EtOH(60 mL) was added phenylhydrazine (4.466 g, 41.3 mmol). After stirringfor 10 minutes, (Z)-4,4,4-trifluorobut-2-enenitrile (5.00 g, 41.3 mmol)was added to the solution. The solution was heated at 95° C. overnight.The solvent was removed under reduced pressure, and the reaction wasquenched with water and extracted with CH₂Cl₂. Extracts were dried overMgSO₄ and concentrated under reduced pressure to about 1/10 volume. Toit was added hexane to form a brown solid, which was filtered to givethe product (5.401 g). The filtrate was purified by silica gelchromatography (with 30-45% EtOAc/hexane) to give1-phenyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-amine the product(1.517 g). Both solids were then combined. (6.918 g, 73%). ¹H NMR (300MHz, CDCl₃) δ 7.24 (m, 2H), 7.09 (m, 2H), 6.92 (m, 1H), 4.39 (m, 1H),4.22 (br, 2H), 3.46 (dd, 1H), 2.87 (q, 1H); LC-MS (ESI) m/z 230 (M+H)⁺.

Example 169A Step 2. A mixture of1-phenyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-3-amine (1.47 g,6.41 mmol) and DDQ (1.748 g, 7.7 mmol) in CH₂Cl₂ (30 mL) was stirred atroom temperature for 4 hours. The crude product was purified by silicagel chromatography twice (with 15-35% and 10-30% EtOAc/hexane aseluants) to afford 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-amine as anoil (0.666 g, 46%). ¹H NMR (300 MHz, CDCl₃) δ 7.42 (m, 5H), 6.18 (s,1H), 3.82 (br, 2H); LC-MS (ESI) m/z 228 (M+H)⁺.

Example 169B: Using the procedure described in Example 161C,1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (0.665 g, 2.9 mmol) andphenyl chloroformate (0.548 g, 3.5 mmol) were reacted in the presence ofK₂CO₃ (0.691 g, 5 mmol) in THF (20 mL) and purified by silica gelchromatography with 10-20% EtOAc/hexane as eluants to afford phenyl1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamte as a solid (0.794g, 79%). ¹H NMR (300 MHz, CDCl₃) δ 7.97 (br, 1H), 7.38-7.46 (m, 7H),7.14-7.29 (m, 4H); LC-MS (ESI) m/z 348 (M+H)⁺.

Example 169C: A mixture of phenyl1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate (0.115 g, 0.33mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A(0.098 g, 0.33 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6mL) was heated at 50° C. for 12 hours and 60° C. for 6 hours. LC-MSshowed the reaction was not complete. Therefore, to it was added4-(dimethylamino)pyridine (0.03 g) and heated at 60° C. for 5 hours. Thecrude product was purified by silica gel chromatography withEtOAc/hexane as eluants to afford the title compound as solid (0.061 g,34%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.47 (s, 1H), 8.99 (s, 1H), 8.57 (s,1H), 7.57 (m, 7H), 7.40 (m, 2H), 7.26 (d, 1H), 7.12 (s, 1H), 6.96 (d,1H), 4.00 (s, 3H), 3.99 (s, 3H); LC-MS (ESI) m/z 551 (M+H)⁺.

Example 170 Preparation of1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]urea

The title compound was prepared as described in Example 169C, usingphenyl 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate describedin Example 169B (0.115 g, 0.33 mmol),3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.103 g,0.33 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL), toafford1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]ureaas solid (0.084 g, 45%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.47 (s, 1H), 9.01(s, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.55 (m, 6H), 7.45 (t, 1H), 7.36(s, 1H), 7.35 (s, 1H), 7.28 (s, 1H), 7.14 (s, 1H), 4.00 (s, 6H); LC-MS(ESI) m/z 567 (M+H)⁺.

Example 171 Preparation of1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]ure

Example 171A: According to the procedure described in Example 161A Step3, using (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2.747 g, 15mmol), (4-fluorophenyl)hydrazine hydrochloride (2.439 g, 15 mmol), andtriethylamine (2.03 g, 20 mmol) at 95° C. for 8 hours, which waspurified by silica gel chromatography with 5-25% EtOAc/hexane as eluantsto afford 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine assolid (2.346 g, 64%). ¹H NMR (300 MHz, CDCl₃) δ 7.55 (m, 2H), 7.20 (m,2H), 5.87 (s, 1H), 3.87 (br, 2H); LC-MS (ESI) m/z 246 (M+H)⁺.

Example 171B: According to the procedure described in Example 161C, to asolution of 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine(2.346 g, 9.57 mmol) in THF (25 mL) and K₂CO₃ (2.63 g, 19 mmol) wasadded phenyl chloroformate (1.948 g, 12.4 mmol). The crude product waspurified by silica gel chromatography (with 5-20% EtOAc/hexane aseluants) to afford phenyl1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate as solid(2.772 g, 79%). ¹H NMR (300 MHz, CDCl₃) δ 7.54 (m, 2H), 7.40 (m, 2H),7.27 (m, 3H), 7.14 (m, 2H), 6.97 (br, 1H), 6.85 (s, 1H); LC-MS (ESI) m/z366 (M+H)⁺.

Example 171C: The title compound was prepared as described in Example162B, using phenyl1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamatedescribed in Example 171B (0.146 g, 0.4 mmol),3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g,0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), toafford1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]ureaas solid (0.203 g, 89%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 8.79(s, 1H), 8.55 (d, 1H), 7.68 (m, 2H), 7.55 (m, 2H), 7.41 (m, 4H), 7.20(d, 1H), 6.96 (d, 1H), 6.85 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H); LC-MS(ESI) m/z 569 (M+H)⁺.

Example 172 Preparation of1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea

Example 172A. According to the procedure described in Example 161A Step3, (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2.747 g, 15mmol), p-tolylhydrazine hydrochloride (2.379 g, 15 mmol) andtriethylamine (2.03 g, 20 mmol) were heated at 95° C. for 8 hours. Thecrude product was purified by silica gel chromatography with 5-25%EtOAc/hexane as eluants to afford1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-amine as solid (2.237 g,62%). ¹H NMR (300 MHz, CDCl₃) δ 7.42 (d, 2H), 7.30 (d, 2H), 5.84 (s,1H), 3.88 (br, 2H), 2.41 (s, 3H); LC-MS (ESI) m/z 242 (M+H)⁺.

Example 172B: According to the procedure described in Example 161C, to asolution of 1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (2.237 g,9.57 mmol) in THF (25 mL) and K₂CO₃ (2.48 g, 18.5 mmol) was added phenylchloroformate (1.887 g, 12.1 mmol). The crude product was purified bysilica gel chromatography with 5-20% EtOAc/hexane as eluants to affordphenyl 1-p-Tolyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate as solid(3.614 g, 94%). ¹H NMR (300 MHz, CDCl₃) δ 7.40 (m, 6H), 7.26 (m, 2H),7.24 (m, 2H), 6.86 (s, 1H), 2.46 (s, 3H); LC-MS (ESI) m/z 362 (M+H)⁺.

Example 172C: According to the procedure described in Example 162B, theintermediate phenyl1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate from the previousstep (0.145 g, 0.4 mmol) was reacted with3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g,0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), toafford1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]ureaas a solid (0.134 g, 59%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H),8.75 (s, 1H), 8.55 (d, 1H), 7.55 (m, 2H), 7.39 (m, 6H), 7.19 (d, 1H),6.95 (d, 1H), 6.84 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 2.41 (s, 3H);LC-MS (ESI) m/z 565 (M+H)⁺.

Example 173 Preparation of1-(4-tert-butylphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

To 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg,0.3 mmol) in DMF (3 mL) was added 4-tert-butylphenyl isocyanate (54 μL,0.3 mmol) and the solution stirred at 50° C. for 4 h. The reaction wasallowed to cool to room temperature, diluted with H₂O, and extractedwith EtOAc. The organic layer was washed with brine, dried over MgSO₄,filtered, concentrated in vacuo, and purified by column chromatography(25-100% EtOAc/hexanes) to give1-(4-tert-butylphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(54 mg, 0.11 mmol, 38%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.65(s, 1H), 8.57 (s, 1H), 7.60 (s, 1H), 7.56 (s, 1H), 7.40-7.21 (m, 7H),6.91 (d, 1H), 3.99 (s, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 473 (M+H)⁺.

Example 174 Preparation of1-(4-tert-butylphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg,0.3 mmol) was reacted with 4-tert-butylphenyl isocyanate (54 uL, 0.3mmol) as described in Example 173 to give1-(4-tert-butylphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(40 mg, 0.08 mmol, 27%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.84 (s, 1H), 8.70(s, 1H), 8.65 (s, 1H), 7.84 (s, 1H), 7.51 (d, 1H), 7.45-7.20 (m, 8H),3.99 (s, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 489 (M+H)⁺.

Example 175 Preparation of1-(4-chlorophenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

In a sealed reaction vessel, 3-(6,7-dimethoxyquinazolin-4-yloxy)anilinefrom Example 113A (100 mg, 0.34 mmol) was dissolved in 10 mL of dry THF.To this solution was added 4-chlorophenyl isocyanate (61 mg, 0.4 mmol).The reaction was heated to 80° C. for 2 hours. The solution was thenconcentrated to dryness and purified by silica gel chromatographyeluting with an ethyl acetate/dichloromethane gradient 5-30% over 16column volumes. The major peak was concentrated and recrystallized withethyl acetate/hexanes, and the solid collected by vacuum filtration togive 26.53 mg. ¹H (DMSO-d6) 8.9 (m, 2H), 8.5 (s, 1H), 7.8-7.2 (m, 9H),6.9 (m, 1H), 4.1 (s, 6H) LCMS (ESI) m/z 515 (M+H)

Example 176 Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Using the procedure for Example 175 the title compound was synthesizedsubstituting 4-chloro-3-trifluoromethyl-phenyl isocyanate (89 mg, 0.40mmol) for 4-chlorophenyl isocyanate. Isolation and purification wasaccomplished using the identical procedure to give 21.7 mg. ¹H (DMSO-d6)9.35 (s, 1H), 9.15 (s, 1H), 8.60 (s, 1H), 8.10 (s, 1H), 7.60 (m, 4H),7.5-7.2 (m, 3H), 6.95 (m, 1H), 3.99 (s, 6H). LCMS (ESI) m/z 519 (M+H)

Example 177 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea

Using the procedure for Example 175 the title compound was synthesizedsubstituting 4-trifluoromethoxy phenyl isocyanate (82 mg, 0.40 mmol) for4-chlorophenyl isocyanate. Isolation and purification was accomplishedusing the identical procedure to give 21.7 mg. ¹H (DMSO-d6) 8.98 (s,1H), 8.56 (s, 1H), 7.7-7.2 (m, 9H), 6.95 (m, 1H), 3.99 (s, 6H). LCMS(ESI) m/z 501 (M+H)

Example 178 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-methoxyphenyl)urea

Using the procedure for Example 175 the title compound was synthesizedsubstituting 3-methoxy phenyl isocyanate (60 mg, 0.40 mmol) for4-chlorophenyl isocyanate. Isolation and purification was accomplishedusing the identical procedure to give 13.4 mg. ¹H (DMSO-d6) 8.88 (s,1H), 8.76 (s, 1H), 8.57 (s, 1H), 7.59 (m, 2H), 7.40 (m, 2H), 7.18 (m,3H), 9.93 (m, 2H), 6.55 (m, 1H), 4.00 (s, 6H), 3.71 (s, 3H). LCMS (ESI)m/z 447 (M+H).

Example 179 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-ethoxyphenyl)urea

Using the procedure for Example 175 the title compound was synthesizedsubstituting 3-ethoxyphenyl isocyanate (56 mg, 0.34 mmol) for4-chlorophenyl isocyanate. Isolation and purification was accomplishedby silica gel chromatography eluting with a methanol-dichloromethane0-15% over 70 minutes to give 47 mg. ¹H (DMSO-d6) 8.85 (s, 1H), 8.71 (s,1H), 8.55 (s, 1H), 7.60 (m, 2H), 7.39 (m, 2H), 7.21 (m, 3H), 6.9 (m,2H), 5.75 (m, 1H), 4.0 (m, 8H), 1.30 (m, 3H). LCMS (ESI) m/z 461 (M+H).

Example 180 Preparation of1-(3-chloro-4-methoxyphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Using the procedure for Example 175 the title compound was synthesizedsubstituting 3-chloro-4-methoxyphenyl isocyanate (63 mg, 0.34 mmol) for4-chlorophenyl isocyanate. Isolation and purification was accomplishedby silica gel chromatography eluting with a methanol-dichlromethane0-15% over 70 minutes to give 107 mg. ¹H (DMSO-d6) 8.87 (s, 1H), 8.70(s, 1H), 8.56 (s, 1H), 7.65 (s, 1H), 7.56 (s, 2H), 7.40 (m, 2H), 7.2 (m,2H), 7.1 (d, 1H), 6.90 (d, 1H), 4.0 (s, 6H), 3.80 (s, 3H). LCMS (ESI)m/z 481 (M+H)

Example 181 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

Using the procedure for Example 175 the title compound was synthesizedsubstituting 3-trifluoromethyl phenyl isocyanate (60 μL, 0.34 mmol) for4-chlorophenyl isocyanate. Isolation and purification was accomplishedby trituration with hexane to give 112 mg. ¹H (DMSO-d6) 9.13 (s, 1H),9.02 (s, 1H), 8.56 (s, 1H), 8.01 (s, 1H), 7.7-7.5 (m, 4H), 7.5-7.2 (m,4H), 6.93 (1H), 3.99 (s, 6H). LCMS (ESI) m/z 485 (M+H)

Example 182 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-phenylurea

To 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg,0.3 mmol) in THF (3 mL) was added phenyl isocyanate (33 uL, 0.3 mmol)and the solution stirred at room temperature overnight. The reaction wasconcentrated in vacuo, diluted with EtOAc, and filtered to give1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-phenylurea (63 mg, 0.15mmol, 50%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.88 (s, 1H), 8.74 (s, 1H), 8.57(s, 1H), 7.61-7.56 (m, 2H), 7.48-7.35 (m, 4H), 7.32-7.21 (m, 3H),7.02-7.89 (m, 2H), 3.99 (s, 6H); LC-MS (ESI) m/z 417 (M+H)⁺.

Example 183 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea

The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3mmol) and 4-(trifluoromethyl)phenyl isocyanate (42 uL, 0.3 mmol) usingthe procedure in Example 182 to give1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea(119 mg, 0.25 mmol, 82%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.18 (s, 1H), 9.03(s, 1H), 8.57 (s, 1H), 7.68-7.62 (m, 4H), 7.61-7.55 (m, 2H), 7.44-7.37(m, 2H), 7.28 (d, 1H), 6.95 (d, 1H), 3.99 (s, 6H); LC-MS (ESI) m/z 485(M+H)⁺.

Example 184 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(4-(trifluoromethyl)phenyl)urea

The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg,0.3 mmol) and 4-(trifluoromethyl)phenyl isocyanate (42 uL, 0.3 mmol)using the procedure in Example 182 to give1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(4-(trifluoromethyl)phenyl)urea(130 mg, 0.26 mmol, 87%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.19 (s, 1H), 9.03(s, 1H), 8.70 (s, 1H), 7.83 (s, 1H), 7.68-7.60 (m, 4H), 7.56 (d, 1H),7.44 (t, 1H), 7.35 (d, 2H), 7.27 (d, 1H), 3.99 (s, 6H); LC-MS (ESI) m/z501 (M+H)⁺.

Example 185 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg,0.3 mmol) and 3-(trifluoromethyl)phenyl isocyanate (42 uL, 0.3 mmol)using the procedure in Example 182 to give1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(109 mg, 0.22 mmol, 73%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.13 (s, 1H), 9.03(s, 1H), 8.70 (s, 1H), 8.01 (s, 1H), 7.84 (s, 1H), 7.62-7.41 (m, 4H),7.39-7.24 (m, 4H), 3.99 (s, 6H); LC-MS (ESI) m/z 501 (M+H)⁺.

Example 186 Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg,0.3 mmol) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (66 mg, 0.3mmol) using the procedure in Example 182 to give1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(113 mg, 0.21 mmol, 70%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (s, 1H), 9.08(s, 1H), 8.70 (s, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 7.66-7.54 (m, 3H),7.44 (t, 1H), 7.35 (s, 1H), 7.34 (s, 1H), 7.28 (d, 1H), 3.99 (s, 6H);LC-MS (ESI) m/z 535 (M+H)⁺.

Example 187 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea

3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (200 mg,0.639 mmol) was reacted with phenyl3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (253 mg,0.959 mmol) according to the method described for1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)ureain Example 122B, except the reaction mixture was stirred at roomtemperature for 72 h. Purification via trituration with methanolafforded1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)ureaas a colorless solid (142 mg, 46%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.43(brs, 1H), 9.13 (brs, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.57 (m, 1H),7.46 (m, 1H), 7.30-7.35 (m, 3H), 6.16 (s, 1H), 3.99 (s, 6H), 1.67 (d,J=21 Hz, 6H); LC-MS (ESI) m/z 484 (M+H)⁺.

Example 188 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)urea

Following the procedure described in Example 138B with3-fluoro-4-(trifluoromethyl)phenylcarbamate as described in Example 150(135 mg, 0.45 mmol) and using3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg,0.3 mmol). To this mixture diisopropylethyl amine (58 mg, 0.45 mmol) andDMAP (3.7 mg, 0.03 mmol) the reaction was heated at 50° C. overnight.The reaction was concentrated to dryness and triturated withdichloromethane. The resulting solid was collected by vacuum filtrationto give 156 mg. ¹H NMR (300 MHz, DMSO-d₆) δ 9.45 (s, 1H), 9.10 (s, 1H),8.79 (s, 1H), 7.8 (s, 1H), 7.6 (m, 2H), 7.5 (m, 1H), 7.35 (m, H), 7.25(m, 4H), 4.00 (s, 6H). LCMS (ESI) m/z 519 (M+H)

Example 189 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)urea

The procedure described in Example 138B was used to react phenyl3-(morpholinomethyl)-5-(trifluoromethyl)phenylcarbamate described inexample 151A (140 mg, 0.37 mmol) with3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (77 mg,0.25 mmol). To this solution was added diisopropylethyl amine (64 μL,0.37 mmol) and DMAP (3.0 mg, 0.03 mmol). The reaction was concentratedto dryness and triturated with methanol to give 47 mg. ¹H NMR (300 MHz,DMSO-d₆) δ 9.15 (s, 1H), 8.98 (s, 1H), 8.70 (s, 1H), 7.88 (d, 2H), 7.55(m, 2H), 7.44 (m, 1H), 7.35 (s, 2H), 7.25 (m, 2H), 4.00 (s, 6H), 3.58(s, 4H), 3.34 (s, 2H), 2.39 (s, 4H). LCMS (ESI) m/z 600 (M+H)

Example 190 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-methoxy-4-(trifluoromethyl)phenyl)urea

Example 190A Step 1: Using the procedure for Example 113C, in a 100 mLround bottomed flask, sodium hydride (276 mg. 11.5 mmol) was suspendedin 30 ml, of a dry THF and cooled to 0° C. To this solution methanol(427 μL, 10.56 mmol) was added and stirred for 30 minutes. This solution2-fluoro-4-nitro-1-trifluoromethyl-benzene (2.0 g, 9.6 mmol) was addedas a 2 mL THF solution. The reaction was allowed to warm to roomtemperature overnight with stirring. The reaction was concentrated andthen partitioned between ethyl acetate and water, extracting twice. Theextracts were dried with magnesium sulfate, filtered and concentrated.The nitro compound was purified by silica gel chromatography using agradient of ethyl acetate/hexane 0-50% over 60 minutes. The main peakwas collected, and concentrated to afford2-methoxy-4-nitro-1-trifluoromethyl-benzene as an oil weighing 1.16 g.¹H NMR (300 MHz, DMSO-d₆) δ 8.0-7.9 (m, 3H), 3.9 (s, 3H)

Example 190A Step 2: The nitro compound (1.16 g, 5.24 mmol) from theprevious was dissolved in 30 mL of methanol and 10% palladium on carbon(100 mg) was added. The solution was evacuated and purged with hydrogenthree times, then stirred under hydrogen overnight. This solution wasthen filtered through celite, and concentrated to an oil to give3-methoxy-4-trifluoromethyl-phenylamine; 1H NMR (300 MHz, DMSO-d₆) δ 7.1(d, 1H), 6.4 (s, 1H), 6.1 (m, 1H), 5.8 (s, 2H), 3.7 (s, 3H).

Example 190B: The amine from the previous step (831 mg, 3.75 mmol) wasdissolved in 15 ml of THF, to this solution potassium carbonate (674 mg,4.88 mmol) was added followed by phenyl chloroformate (647 mg, 4.13mmol) dropwise as a THF solution. The reaction was stirred overnight atroom temperature, then filtered through celite, concentrated andpartitioned between ethyl acetate and water, and extracted twice. Theextracts were combined and dried with magnesium sulfate, filtered andconcentrated to a solid. The solid was triturated with 10% ether inhexane. The resulting solid weighing 684 mg was found to be phenyl3-methoxy-4-(trifluoromethyl)phenyl carbamate. ¹H NMR (300 MHz, DMSO-d₆)δ 10.6 (s, 1H), 7.58 (d, 1H), 7.48 (m, 3H), 7.2 (m, 3H), 7.1 (d, 1H),3.8 (s, 3H)

Example 190C: The procedure described in Example 138B was used to reactphenyl 3-methoxy-4-(trifluoromethyl)phenylcarbamate from the previousstep (140 mg, 0.45 mmol) with3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg,0.30 mmol). To this solution was added diisopropylethyl amine (80 μL,0.46 mmol) and DMAP (4.0 mg, 0.03 mmol). The reaction was concentratedto dryness and triturated with dichloromethane to give 44 mg of finalcompound. ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (s, 1H), 8.93 (s, 1H), 8.70(s, 1H), 7.90 (s, 1H), 7.6-7.40 (m, 4H), 7.35 (m, 3H), 7.00 (m, 1H),4.00 (s, 6H), 3.84 (s, 3H). LCMS (ESI) m/z 531 (M+H)

Example 191 Preparation of1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]urea

Using the procedure described in Example 162B, phenyl5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate as describedin Example 162A (0.089 g, 0.3 mmol) was reacted with3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.094 g,0.3 mmol), and 4-(dimethylamino)pyridine (0.03 g) in THF (6 mL), toafford1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]ureaas solid (0.048 g, 31%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.71 (s, 1H), 9.02(s, 1H), 8.70 (s, 1H), 7.85 (d, 1H), 7.52 (d, 1H), 7.46 (t, 1H), 7.35(d, 2H), 7.29 (d, 1H), 6.78 (s, 1H), 4.72 (s, 2H), 4.56 (s, 2H), 3.99(s, 6H), 1.29 (s, 3H); LC-MS (ESI) m/z 516 (M+H)⁺.

Example 192 Preparation of1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea

Using the procedure described in Example 159B, using phenyl1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described inExample 161C (0.139 g, 0.4 mmol),3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g,0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50°C. for 6 hours, to afford1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]ureaas solid (0.100 g, 44%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.33 (s, 1H), 8.80(s, 1H), 8.70 (s, 1H), 7.78 (s, 1H), 7.53 (m, 5H), 7.25-7.48 (m, 5H),6.81 (s, 1H), 3.99 (s, 6H); LC-MS (ESI) m/z 567 (M+H)⁺.

Example 193 Preparation of1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea

Using the procedure described in Example 159B, phenyl1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate as described inExample 164B (0.114 g, 0.4 mmol),3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g,0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50°C. for 3 hours, to afford1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]ureaas solid (0.035 g, 17%). ¹H NMR (300 MHz, CDCl₃) δ 9.45 (br, 1H), 8.77(s, 1H), 7.80 (s, 1H), 7.63 (d, 1H), 7.44 (t, 1H), 7.35 (m, 2H), 7.28(s, 1H), 7.21 (s, 1H), 6.31 (s, 1H), 4.08 (s, 3H), 4.06 (s, 3H), 3.91(s, 3H); LC-MS (ESI) m/z 505 (M+H)⁺.

Example 194 Preparation of1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]urea

Using the procedure described in Example 159B, phenyl1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate described inExample 165A (0.114 g, 0.4 mmol) was reacted with3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g,0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) at 50°C. for 3 hours, to afford1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]ureaas solid (0.035 g, 17%). ¹H NMR (300 MHz, CDCl₃) δ 9.43 (br, 1H), 8.77(s, 1H), 7.80 (m, 1H), 7.63 (d, 1H), 7.44 (t, 1H), 7.38 (m, 2H), 7.28(s, 1H), 7.20 (s, 1H), 6.31 (s, 1H), 4.08 (s, 3H), 4.06 (s, 3H), 3.91(s, 3H); LC-MS (ESI) m/z 505 (M+H)⁺.

Example 195 Preparation of ethyl2-(3-tert-butyl-5-{3-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]ureido}-1H-pyrazol-1-yl)acetate

Using the procedure described in Example 159B, using ethyl2-[3-tert-butyl-5-(phenoxycarbonylamino)-1H-pyrazol-1-yl]acetatedescribed in Example 166A (0.138 g, 0.4 mmol),3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g,0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) at 50°C. for 7 hours, to afford ethyl2-(3-tert-butyl-5-{3-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]ureido}-1H-pyrazol-1-yl)acetateas solid (133 mg, 59%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.70(s, 1H), 8.60 (m, 1H), 7.83 (s, 1H), 7.51 (d, 1H), 7.43 (t, 1H), 7.35(s, 1H), 7.34 (s, 1H), 7.25 (d, 1H), 6.12 (s, 1H), 4.85 (s, 2H), 4.15(q, 2H), 3.99 (s, 6H), 1.20 (s and t, 12H); LC-MS (ESI) m/z 565 (M+H)⁺.

Example 196 Preparation of1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]urea

Using the procedure described in Example 159B, phenyl3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamateas described in Example 167B (0.186 g, 0.5 mmol),3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g,0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50°C. for 6 hours, to afford1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]ureaas solid (95 mg, 40%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H), 8.69(s, 1H), 8.56 (s, 1H), 7.80 (s, 1H), 7.23-7.80 (m, 10H), 6.51 (s, 1H),4.71 (m, 2H), 4.55 (m, 2H), 3.99 (s, 6H), 1.31 (s, 3H); LC-MS (ESI) m/z591 (M+H)⁺.

Example 197 Preparation of1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]urea

Example 197A: Using the procedure described in Example 159B, usingphenyl 3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamatedescribed in Example 168B (0.115 g, 0.33 mmol),3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.103 g,0.33 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50°C. for 5 hours, to afford1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]ureaas solid (123 mg, 64%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (br, 1H), 8.69(s, 1H), 8.54 (s, 1H), 7.80 (s, 1H), 7.54 (m, 4H), 7.23-7.45 (m, 5H),7.24 (d, 1H), 6.42 (s, 1H), 3.99 (s, 6H), 3.25 (q, 2H), 1.46 (s, 6H),1.04 (t, 3H); LC-MS (ESI) m/z 539 (M−OEt)⁺.

Example 198 Preparation of1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea

The title compound was prepared as described in Example 162B, usingphenyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamatedescribed in Example 171B (0.146 g, 0.4 mmol),3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g,0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), toafford1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]ureaas solid (184 mg, 79%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 8.79(s, 1H), 8.69 (d, 1H), 7.79 (s, 1H), 7.68 (m, 2H), 7.46 (m, 4H), 7.42(s, 1H), 7.35 (s, 1H), 7.27 (d, 1H), 6.87 (s, 1H), 3.99 (s, 6H); LC-MS(ESI) m/z 585 (M+H)⁺.

Example 199 Preparation of1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea

The title compound was prepared as described in Example 162B, usingphenyl 1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate describedin Example 172B (0.145 g, 0.4 mmol),3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g,0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), toafford1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]ureaas solid (0.192 g, 83%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 8.74(s, 1H), 8.69 (d, 1H), 7.78 (s, 1H), 7.45 (m, 6H), 7.35 (s, 1H), 7.33(s, 1H), 7.25 (d, 1H), 6.85 (s, 1H), 3.99 (s, 6H), 2.41 (s, 3H); LC-MS(ESI) m/z 581 (M+H)⁺.

Example 200 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)urea

The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg,0.3 mmol) and 3-(2-methoxyethoxy)-5-(trifluoromethyl)phenylcarbamatefrom Example 117A (160 mg, 0.45 mmol) using Example 115C to give1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)urea(118 mg, 0.21 mmol, 69%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.09 (s, 1H), 9.04(s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.55 (d, 1H), 7.50-7.41 (m, 2H),7.35 (s, 1H), 7.34 (s, 1H), 7.29-7.23 (m, 2H), 6.87 (s, 1H), 4.19-4.11(m, 2H), 4.00 (s, 6H), 3.70-3.63 (m, 2H), 3.31 (s, 3H); LC-MS (ESI) m/z575 (M+H)⁺.

Example 201 Preparation of1-(5-Cyclopentylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared as described in Example 113C by using3-(6,7-dimethoxyquinazolin-4-ylthio)aniline described in Example 115B(114 mg, 0.32 mmol) and phenyl 5-isopropylisoxazol-3-ylcarbamatedescribed in Example 135A (130 mg, 0.48 mmol). Precipitation of thedesired product detected completion of reaction. The solid was filteredoff and washed with diethyl ether to give1-(5-cyclopentylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(126 mg, 80%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s,1H), 9.04 (s, 1H), 8.69 (s, 1H), 7.84 (s, 1H), 7.50-7.44 (m, 2H),7.36-7.28 (m, 3H), 6.51 (s, 1H), 3.99 (s, 6H), 3.21-3.01 (m, 1H),2.02-2.00 (m, 2H), 1.67-1.64 (m, 6H); LC-MS (ESI) m/z 492 (M+H)⁺.

Example 202 Preparation of1-(3-tert-butylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

The title compound was prepared as described in Example 113C by using3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline described inExample 117B (102 mg, 0.3 mmol) and phenyl3-tert-butylisoxazol-5-ylcarbamate described in Example 132A (101 mg,0.39 mmol) to give1-(3-tert-butylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea(103 mg, 68%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.19 (s,1H), 9.03 (s, 1H), 8.56 (s, 1H), 7.58 (s, 2H), 7.42 (t, 2H), 7.30 (d,1H), 6.99 (d, 1H), 6.04 (s, 1H), 4.34 (bs, 2H), 3.99 (s, 3H), 3.77 (bs,2H), 3.36 (s, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 508 (M+H)⁺.

Example 203 Preparation of1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(5-phenylisoxazol-3-yl)urea

According to the procedure described in Example 113C,3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (102 mg, 0.3 mmol) in THF (1.5 mL) was treated withN,N-diisopropylethylamine (68 μl, 0.39 mmol), 4-(dimethylamino)pyridine(1.8 mg, 0.015 mmol) and phenyl 5-phenylisoxazol-3-ylcarbamate fromExample 113B (109 mg, 0.39 mmol). The reaction mixture was heated to 50°C. for 4 h. After cooling to room temperature, the mixture waspartitioned between chloroform and a saturated solution of sodiumbicarbonate. The water phase was back extracted three times withchloroform and the organics combined and dried (MgSO₄). Concentrationunder reduced pressure gave a residue which was purified by preparativeHPLC (phenylhexyl reverse phase column). The obtained solid wastriturated with anhydrous diethyl ether to afford1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(5-phenylisoxazol-3-yl)ureaas a white solid (110 mg, 70%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.74 (s,1H), 9.06 (s, 1H), 8.57 (s, 1H), 7.86 (d, 2H), 7.62-7.53 (m, 5H), 7.51(t, 2H), 7.28 (m, 2H), 6.99 (d, 1H), 4.34 (bs, 2H), 4.00 (s, 3H), 3.77(bs, 2H), 3.35 (s, 3H); LC-MS (ESI) m/z 528 (M+H)⁺.

Example 204 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-phenylisoxazol-5-yl)urea

The title compound was prepared according to the procedure described inExample 207 by using3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (102 mg, 0.3 mmol) and phenyl 3-phenylisoxazol-5-ylcarbamate fromExample 114B (109 mg, 0.45 mmol) to afford1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-phenylisoxazol-5-yl)ureaas a white solid upon trituration with methanol (26 mg, 16%). ¹H NMR(300 MHz, DMSO-d₆) δ 10.41 (s, 1H), 9.13 (s, 1H), 9.13 (s, 1H), 7.83 (m,2H), 7.59 (d, 2H), 7.50-7.41 (m, 5H), 7.33 (d, 2H), 7.00 (d, 1H), 6.56(s, 1H), 4.34 (bs, 2H), 4.00 (s, 3H), 3.35 (s, 3H); LC-MS (ESI) m/z 528(M+H)⁺.

Example 205 Preparation of1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(morpholine-4-carbonyl)-5-(trifluoromethyl)phenyl)urea

3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (103 mg, 0.3 mmol) was reacted with phenyl3-(morpholine-4-carbonyl)-5-(trifluoromethyl)phenyl)carbamate describedin Example 149A (114 mg, 0.42 mmol) using the procedure in Example 115C.The final product was purified by column chromatography (2-10% MeOH/DCM)to give1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(3-(morpholine-4-carbonyl)-5-(trifluoromethyl)phenyl)urea(115 mg, 0.18 mmol, 60%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (s, 1H), 9.13(s, 1H), 8.56 (s, 1H), 8.00 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 7.57(s, 1H), 7.43-7.37 (m, 2H), 7.35-7.36 (m, 2H), 6.96 (d, 1H), 4.38-4.32(m, 2H), 4.00 (s, 3H), 3.80-3.51 (m, 10H), 3.33 (s, 3H); LC-MS (ESI) m/z642 (M+H)⁺.

Example 206 Preparation of1-(5-isopropylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

The title compound was prepared as described in Example 113C by using3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (102 mg, 0.3 mmol) and phenyl 5-isopropylisoxazol-3-ylcarbamatedescribed in Example 133A (110 mg, 0.45 mmol) to give1-(5-isopropylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea(69.5 mg, 47%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.52 (s,1H), 9.05 (s, 1H), 8.55 (s, 1H), 7.52 (s, 2H), 7.45-7.36 (m, 2H), 7.25(d, 1H), 6.99 (d, 1H), 6.5 (s, 1H), 4.35 (bs, 2H), 4.00 (s, 3H), 3.89(bs, 2H), 3.36 (s, 3H), 3.01-2.99 (m, 1H), 1.22 (d, 6H); LC-MS (ESI) m/z494 (M+H)⁺.

Example 207 Preparation of1-(3-cyclopentylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

The title compound was prepared as described in Example 113C by using3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (104 mg, 0.35 mmol), phenyl 3-cyclopentylisoxazol-5-ylcarbamatedescribed in Example 163A (124 mg, 0.45 mmol) andN,N-diisopropylethylamine (73 μl, 0.42 mmol) to give1-(3-cyclopentylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea(51.72 mg, 28%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.18 (s,1H), 9.05 (s, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.50-7.35 (m, 2H), 7.30(d, 1H), 7.00 (d, 1H), 5.95 (s, 1H), 4.34 (bs, 2H), 3.99 (s, 3H), 3.77(bs, 2H), 3.34 (s, 3H), 3.11-2.99 (m, 1H), 2.10-1.80 (m, 2H), 1.75-1.50(m, 6H); LC-MS (ESI) m/z 520 (M+H)⁺.

Example 2081-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]urea

Using the procedure described in Example 159B, phenyl1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate described inExample 165A (0.114 g, 0.4 mmol) was reacted with3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF(6 mL) at 50° C. for 3 hours, to afford1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]ureaas solid (0.028 g, 13%). ¹H NMR (300 MHz, CDCl₃) δ 9.53 (br, 1H), 8.63(s, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 7.41 (t, 1H), 7.32 (m, 2H), 7.12(s, 1H), 7.01 (d, 1H), 6.28 (s, 1H), 4.36 (t, 2H), 4.04 (s, 3H), 3.92 (sand t, 5H), 3.50 (s, 3H); LC-MS (ESI) m/z 533 (M+H)⁺.

Example 209 Preparation of1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

The procedure in 138B was used to react the carbamate from Example 157A(123 mg, 0.45 mmol) with3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (103 mg, 0.30 mmol). To this solution was added diisopropylethylamine (78 μL, 0.45 mmol) and DMAP (3.6 mg, 0.03 mmol). The reaction wasconcentrated to dryness. The resulting oil purified by silica gelchromatography eluting with ethyl acetate/dichloromethane 10-50% over 60minutes. The main peak concentrated to a solid weighing 126 mg. ¹H(DMSO-d6) 9.10 (s, 1H), 8.70 (s, 2H), 7.65 (m, 2H), 7.50 (m, 2H), 7.30(m, 1H), 7.15 (s, 1H), 6.95 (m, 1H), 6.00 (s, 1H), 4.40 (s, 2H), 4.00(s, 3H), 3.85 (s, 2H), 3.60 (s, 3H), 3.40 (s, 3H), 1.25 (s, 9H). LCMS(ESI) m/z 521 (M+H)

Example 210 Preparation of1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

The procedure for Example 138B was used to react phenyl3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate described in Example 154A(151 mg, 0.45 mmol) with3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (103 mg, 0.30 mmol). To this solution was added diisopropylethylamine (80 μL, 0.45 mmol) and DMAP (4 mg, 0.03 mmol). After heating for 2hours the reaction was concentrated to dryness. The resulting solid waschromatographed using silica gel (eluting with an ethyl acetate/hexanegradient 0-85%). The main peak was concentrated to give 59 mg. ¹H(DMSO-d6) 9.23 (s, 1H), 8.54 (s, 1H), 8.47 (s, 1H), 7.55 (m, 6H), 7.40(m, 3H), 7.18 (s, 1H), 6.95 (m, 1H), 6.35 (s, 1H), 4.34 (m, 2H), 3.98(s, 3H), 3.77 (m, 2H), 3.34 (s, 3H), 1.25 (s, 9H). LCMS (ESI) m/z 583(M+H)

Example 211 Preparation of1-(3-(1,1-difluoroethyl)isoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

The procedure for Example 138B was used substituting phenyl3-(1,1-difluoroethyl)isoxazol-5-yl carbamate described in Example 152A(80 mg, 0.30 mmol) and3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (100 mg, 0.29 mmol). To this solution was added diisopropylethylamine (75 μL, 0.43 mmol) and DMAP (5 mg, 0.04 mmol). After heating for 1hour the reaction was concentrated to dryness. The resulting solid waspurified by reversed phase HPLC using a phenyl hexyl column and elutingwith an acetonitrile/water gradient 40-75% over 60 minutes. The majorpeak was concentrated and then lypholyzed to give 33 mg. ¹H (DMSO-d6)10.08 (s, 1H), 8.59 (s, 1H), 7.60 (m, 2H), 7.57 (m, 3H), 6.95 (m, 1H),6.24 (s, 1H), 4.35 (m, 2H), 4.00 (s, 3H), 3.85 (m, 2H), 3.35 (s, 3H),2.00 (t, 3H); LCMS (ESI) m/z 516 (M+H).

Example 212 Preparation of1-[3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}urea

Using the procedure described in Example 159B, phenyl3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate described inExample 168B (0.115 g, 0.33 mmol),3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (0.112 g, 0.33 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF(6 mL) at 50° C. for 5 hours, to afford1-[3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}ureaas solid (0.116 g, 57%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (br, 1H), 8.55(s, 2H), 7.56 (m, 6H), 7.41 (m, 3H), 7.18 (d, 1H), 6.94 (d, 1H), 6.41(s, 1H), 4.34 (m, 2H), 3.98 (s, 3H), 3.77 (m, 2H), 3.35 (s, 3H), 3.24(q, 2H), 1.46 (s, 6H), 1.03 (t, 3H); LC-MS (ESI) m/z 567 (M−OEt)⁺.

Example 213 Preparation of1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}urea

The title compound was prepared as described in Example 162B, usingphenyl 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate asdescribed in Example 162A (0.089 g, 0.3 mmol),3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (0.102 g, 0.3 mmol), and 4-(dimethylamino)pyridine (0.03 g) in THF(6 mL), to afford1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}ureaas solid (0.061 g, 37%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.71 (s, 1H), 9.01(s, 1H), 8.56 (s, 1H), 7.58 (m, 2H), 7.42 (m, 2H), 7.27 (d, 1H), 6.98(d, 1H), 6.77 (s, 1H), 4.71 (s, 2H), 4.56 (s, 2H), 4.35 (m, 2H), 3.99(s, 3H), 3.77 (m, 2H), 3.56 (s 3H), 1.28 (s, 3H); LC-MS (ESI) m/z 544(M+H)⁺.

Example 214 Preparation of1-(3-cyclopropylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

Prepared from 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)anilinefrom Example 117B (90 mg, 0.264 mmol) and phenyl3-cyclopropylisoxazol-5-ylcarbamate from Example 124A (78 mg, 0.317mmol) according to the method described for1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)ureain Example 122B to afford1-(3-cyclopropylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)ureaas a colorless solid (68 mg, 52%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.21(brs, 1H), 9.08 (brs, 1H), 8.55 (s, 1H), 7.56 (s, 2H), 7.38-7.44 (m,2H), 7.29 (m, 1H), 6.99 (m, 1H), 5.77 (s, 1H), 4.35 (m, 2H), 3.99 (s,3H), 3.78 (m, 2H), 3.30 (s, 3H), 1.90 (m, 1H), 0.94-0.98 (m, 2H),0.71-0.73 (m, 2H); LC-MS (ESI) m/z 492 (M+H)⁺.

Example 215 Preparation of1-(3-isopropylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (90 mg, 0.264 mmol) was reacted with phenyl3-isopropylisoxazol-5-ylcarbamate as prepared in Example 122A (78 mg,0.317 mmol) to afford1-(3-isopropylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)ureaas a colorless solid (70 mg, 54%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.30(brs, 1H), 9.14 (brs, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.38-7.44 (m,2H), 7.31 (m, 1H), 6.99 (m, 1H), 5.99 (s, 1H), 4.32-4.35 (m, 2H), 3.99(s, 3H), 3.77-3.78 (m, 2H), 3.35 (s, 3H), 2.90 (septet, J=9 Hz, 1H),1.19 (d, J=9 Hz, 6H); LC-MS (ESI) m/z 494 (M+H)⁺.

Example 216 Preparation of1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-yl)urea

Prepared from 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)anilinefrom Example 117B (60 mg, 0.176 mmol) and phenyl3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-ylcarbamate from Example 123A (56mg, 0.194 mmol) according to the method described for1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)ureain Example 122B to afford1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-yl)ureaas a colorless solid (19 mg, 20%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.70(brs, 1H), 9.38 (brs, 1H), 8.55 (s, 1H), 7.57 (s, 2H), 7.38-7.42 (m,2H), 7.32 (m, 1H), 6.98 (m, 1H), 6.00 (s, 1H), 4.34-4.35 (m, 2H), 3.99(s, 3H), 3.87-3.90 (m, 2H), 3.77-3.78 (m, 2H), 3.42-3.46 (m, 2H), 3.35(s, 3H), 2.88 (m, 1H), 1.76-1.81 (m, 2H), 1.60-1.65 (m, 2H); LC-MS (ESI)m/z 536 (M+H)⁺.

Example 217 Preparation of1-(5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

Prepared from 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)anilinefrom Example 117B (100 mg, 0.293 mmol) and phenyl3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-ylcarbamate described inExample 128A (118 mg, 0.407 mmol) according to the method described for1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)ureain Example 122B to afford1-(5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)ureaas a colorless solid (72 mg, 46%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.61(brs, 1H), 9.03 (brs, 1H), 8.56 (s, 1H), 7.57-7.58 (m, 2H), 7.38-7.43(m, 2H), 7.26 (m, 1H), 6.98 (m, 1H), 6.51 (s, 1H), 4.35 (m, 2H), 3.99(s, 3H), 3.78 (m, 2H), 3.38 (s, 2H), 3.35 (s, 3H), 3.23 (s, 3H), 1.20(s, 6H); LC-MS (ESI) m/z 538 (M+H)⁺.

Example 218 Preparation of1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

Prepared from 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)anilinefrom Example 117B (72 mg, 0.212 mmol) and phenyl3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (56 mg,0.212 mmol) according to the method described for1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)ureain Example 122B to afford1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)ureaas a colorless solid (46 mg, 43%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.45(brs, 1H), 9.12 (brs, 1H), 8.56 (s, 1H), 7.57-7.58 (m, 2H), 7.39-7.45(m, 2H), 7.32 (m, 1H), 7.00 (m, 1H), 6.14 (s, 1H), 4.32-4.35 (m, 2H),3.99 (s, 3H), 3.75-3.78 (m, 2H), 3.35 (s, 3H), 1.67 (d, J=21 Hz, 6H);LC-MS (ESI) m/z 512 (M+H)⁺.

Example 219 Preparation of1-(5-cyclopentylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

The title compound was prepared as described in Example 113C by using3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline described inExample 117B (109 mg, 0.32 mmol) and phenyl5-isopropylisoxazol-3-ylcarbamate described in Example 135A (130 mg,0.48 mmol) to give1-(5-cyclopentylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea(87.11 mg, 52%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.59 (s,1H), 9.04 (s, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.41 (t, 2H), 7.26 (d,1H), 6.98 (d, 1H), 6.50 (s, 1H), 4.34 (bs, 2H), 3.99 (s, 3H), 3.77 (bs,2H), 3.34 (s, 3H), 3.18-3.05 (m, 1H), 2.09-1.99 (m, 2H), 1.70-1.64 (m,6H); LC-MS (ESI) m/z 520 (M+H)⁺.

Example 220 Preparation of1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy],phenyl}-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea

Using the procedure described in Example 159B, using phenyl1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described inExample 164B (0.114 g, 0.4 mmol),3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF(6 mL) at 50° C. for 3 hours, to afford1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]ureaas solid (0.033 g, 15%). ¹H NMR (300 MHz, CDCl₃) δ 9.5 (br, 1H), 8.63(s, 1H), 7.60 (m, 1H), 7.55 (s, 1H), 7.32-7.43 (m, 4H), 7.00 (dd, 1H),6.31 (s, 1H), 4.36 (t, 2H), 4.04 (s, 3H), 3.91 (s and t, 5H), 3.50 (s,3H); LC-MS (ESI) m/z 533 (M+H)⁺.

Example 221 Preparation of1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea

Using the procedure described in Example 159B, using phenyl1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate from Example 161C(0.139 g, 0.4 mmol),3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF(6 mL) at 50° C. for 6 hours, to afford1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]ureaas solid (0.115 g, 48%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 8.81(s, 1H), 8.54 (s, 1H), 7.49-7.62 (m, 7H), 7.38 (m, 2H), 7.20 (d, 1H),6.95 (d, 1H), 6.87 (s, 1H), 4.38 (m, 2H), 3.98 (s, 3H), 3.78 (m, 2H),3.35 (s, 3H); LC-MS (ESI) m/z 595 (M+H)⁺.

Example 222 Preparation of1-(3-fluoro-4-(trifluoromethyl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

The procedure for Example 138B was used reacting3-fluoro-4-(trifluoromethyl)phenylcarbamate carbamate as described inExample 150 (135 mg, 0.45 mmol) with amine3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (102 mg, 0.30 mmol). To this solution was added diisopropylethylamine (80 μL, 0.46 mmol) and DMAP (4.0 mg, 0.03 mmol). The reaction wasconcentrated to dryness and triturated with dichloromethane to give 126mg of1-(3-fluoro-4-(trifluoromethyl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea.¹H (DMSO-d6) 9.50 (s, 1H), 9.15 (s, 1H), 8.60 (s, 1H), 7.70 (m, 2H),7.60 (s, 2H), 7.35 (m, 2H), 7.30 (m, 2H), 7.00 (m, 1H), 4.30 (m, 2H),4.00 (s, 3H), 3.84 (m, 2H), 3.40 (s, 3H). LCMS (ESI) m/z 547 (M+H)

Example 223 Preparation of1-(3-methoxy-4-(trifluoromethyl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

The procedure for Example 138B was used to react with phenyl3-methoxy-4-(trifluoromethyl)phenylcarbamate described in Example 190B(140 mg, 0.45 mmol) with3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (103 mg, 0.30 mmol). To this solution was added diisopropylethylamine (80 μL, 0.46 mmol) and DMAP (4.0 mg, 0.03 mmol). The reaction wasconcentrated to dryness and triturated with dichloromethane to give 52mg. ¹H (DMSO-d6) 9.30 (s, 1H), 9.15 (s, 1H), 8.60 (s, 1H), 7.60 (m, 2H),7.50 (s, 2H), 7.35 (m, 2H), 7.25 (m, 1H), 7.00 (m, 2H), 4.35 (m, 2H),4.00 (s, 3H), 3.84 (s, 3H), 3.70 (m, 2H), 3.40 (m, 3H). LCMS (ESI) m/z559 (M+H)

Example 224 Preparation of ethyl2-[3-tert-butyl-5-(3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}ureido)-1H-pyrazol-1-yl]acetatehydrochloride

Example 224A: Using the procedure described in Example 159B, ethyl2-[3-tert-butyl-5-(phenoxycarbonylamino)-1H-pyrazol-1-yl]acetatedescribed in Example 166A (0.138 g, 0.4 mmol) was reacted with3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF(6 mL) at 50° C. for 7 hours, to afford ethyl2-[3-tert-butyl-5-(3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}ureido)-1H-pyrazol-1-yl]acetateas solid.

Example 224B: The title compound was prepared as described in Example 6,Step B, using ethyl2-[3-tert-butyl-5-(3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}ureido)-1H-pyrazol-1-yl]acetateand 1.0 M HCl/Et₂O solution in CH₂Cl₂ and MeOH, to afford ethyl2-[3-tert-butyl-5-(3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}ureido)-1H-pyrazol-1-yl]acetatehydrochloride as solid (0.185 g, 73%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.30(s, 1H), 8.99 (s, 1H), 8.64 (s, 1H), 7.60 (m, 2H), 7.43 (s, 1H), 7.40(t, 1H), 7.24 (d, 1H), 6.95 (d, 1H), 6.13 (s, 1H), 4.89 (s, 2H), 4.5(br, 3H), 4.36 (m, 2H), 4.15 (q, 2H), 4.00 (s, 3H), 3.78 (m, 2H), 1.20(s and t, 12H); LC-MS (ESI) m/z 593 (M+H)⁺.

Example 225 Preparation of1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]urea

The title compound was prepared as described in Example 169C usingphenyl 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate describedin Example 169B (0.115 g, 0.33 mmol),3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (0.112 g, 0.33 mmol), to afford1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]ureaas solid (0.114 g, 58%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.47 (s, 1H), 8.99(s, 1H), 8.56 (s, 1H), 7.58 (m, 7H), 7.42 (m, 2H), 7.27 (d, 1H), 7.13(s, 1H), 6.97 (d, 1H), 4.35 (m, 2H), 4.00 (s, 3H), 3.78 (m, 2H), 3.35(s, 3H); LC-MS (ESI) m/z 595 (M+H)⁺.

Example 226 Preparation of1-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}urea

The title compound was prepared as described in Example 162B, usingphenyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamatedescribed in Example 171B (0.146 g, 0.4 mmol),3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (0.137 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF(6 mL), to afford1-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}ureaas solid (0.166 g, 68%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 8.79(s, 1H), 8.55 (d, 1H), 7.67 (m, 2H), 7.54 (m, 2H), 7.44 (m, 4H), 7.20(d, 1H), 6.97 (d, 1H), 6.86 (s, 1H), 4.35 (m, 2H), 3.98 (s, 3H), 3.77(m, 2H), 3.35 (s, 3H); LC-MS (ESI) m/z 613 (M+H)⁺.

Example 227 Preparation of1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy],phenyl}-3-[1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea

Using the procedure described in Example 162B, phenyl1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described inExample 172B (0.145 g, 0.4 mmol) was reacted with3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (0.137 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF(6 mL), to afford1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]ureaas solid (0.190 g, 78%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 8.75(s, 1H), 8.54 (s, 1H), 7.55 (m, 2H), 7.36 (m, 6H), 7.19 (d, 1H), 6.95(d, 1H), 6.84 (s, 1H), 4.34 (m, 2H), 3.98 (s, 3H), 3.77 (m, 2H), 3.35(s, 3H), 2.41 (s, 3H); LC-MS (ESI) m/z 609 (M+H)⁺.

Example 228 Preparation of1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}urea

Using the procedure described in Example 159B, phenyl3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamateas described in Example 167B (0.186 g, 0.5 mmol),3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF(6 mL) at 50° C. for 6 hours, to afford1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}ureaas solid (0.106 g, 43%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.57(s, 1H), 8.55 (s, 1H), 7.56 (m, 6H), 7.40 (m, 3H), 7.18 (d, 1H), 6.94(d, 1H), 6.50 (s, 1H), 4.70 (m, 2H), 4.54 (m, 2H), 4.33 (m, 2H), 3.98(s, 3H), 3.78 (m, 2H), 3.35 (s, 3H), 1.30 (s, 3H); LC-MS (ESI) m/z 619(M+H)⁺.

Example 229 Preparation of1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea

Example 229A Step 1: (Trimethylsilyl)diazomethane (21 mL, 2M in diethylether) was added dropwise to a solution of4,4,4-trifluoro-3-oxobutanenitrile (3.79 g, 26 mmol) in anhydrousdiethyl ether (25 mL) previously cooled to 0° C. The resulting mixturewas allowed to slowly warm to room temperature and stirred overnight.The solvent was removed under reduced pressure to give4,4,4-trifluoro-3-methoxybut-2-enenitrile, which was directly used inthe next step without further purification. ¹H NMR (300 MHz, CDCl₃) d5.00 (s, 1H), 4.16 (s, 3H).

Example 229A Step 2: Hydroxylamine hydrochloride (2.88 g, 41. 5 mmol)was dissolved in methanol (20 mL) and cooled to 0° C. in an ice-bath.Sodium methoxide (2.24 g, 41.5 mmol) was added and the resultingsuspension stirred at room temperature for 15 minutes. The suspensionwas cooled to 0° C., 4,4,4-trifluoro-3-methoxybut-2-enenitrile (26 mmol)was added dropwise and the mixture allowed to slowly warm to roomtemperature. The mixture was then heated to 60° C. overnight. The whitesolid was removed by filtration, washed with dichloromethane and thefiltrate concentrated under reduced pressure to afford4,4,4-trifluoro-N′-hydroxy-3-methoxybut-2-enimidamide as a solid, whichwas used directly in the next step without further purification. Thesolid was taken in ethanol (25 mL) and the solution acidified (pH=1)with 37% aqueous hydrochloric acid. The resulting mixture was heated to60° C. for 2 h. Ethanol was removed under reduced pressure and theresidue diluted with dichloromethane. A saturated solution of sodiumbicarbonate was added (pH=14) and the organic phase separated. Theaqueous phase was back extracted three times with dichloromethane, theorganics combined, dried (MgSO₄) and concentrated under reducedpressure. The resulting crude material was purified by silica gelchromatography (dichloromethane/ethyl acetate 95:5) to isolate3-(trifluoromethyl)isoxazol-5-amine (446 mg, 11%) along with5-(trifluoromethyl)isoxazol-3-amine as a minor product. ¹H NMR (300 MHz,CDCl₃) d 5.31 (s, 1H), 5.03 (bs, 2H).

Example 229A: 3-(Trifluoromethyl)isoxazol-5-amine (446 mg, 2.93 mmol) intetrahydrofuran (6 mL) was treated with triethylamine (1.1 mL, 8.2mmol), phenyl choloroformate (0.88 mL, 7.03 mmol) and4-(dimethylamino)pyridine (357 mg, 2.93 mmol). The reaction mixture wasstirred at room for 3 h, then filtered through a celite pad, washed withethyl acetate and concentrated to dryness. The residue was taken intodichloromethane, washed with brine, and the combined organics dried(MgSO₄) and concentrated. The residue was purified by silica gelchromatography (hexane/ethyl acetate 8:2) to give phenyl3-(trifluoromethyl)isoxazol-5-ylcarbamate (269 mg, 33%) as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 7.99 (bs, 1H), 7.4 (t, 2H), 7.35-7.02(m, 3H), 6.7 (s, 1H)

Example 229B: 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)anilinefrom Example 117B (154 mg, 0.41 mmol) and the carbamate from theprevious step (146 mg, 0.54 mmol) were dissolved in tetrahydrofuran (2mL) and treated with N,N-diisopropylethylamine (72 μl, 0.41 mmol). Themixture was stirred at room temperature for 4 h. After addition ofdiethyl ether the precipitating solid was filtered and dried. Thematerial was further purified by preparative HPLC (Phenomenexphenylhexyl reverse phase column) to give1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea(90 mg, 42%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.93 (s,1H), 9.25 (s, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.47-7.42 (m, 2H), 7.34(d, 1H), 7.03 (d, 1H), 6.49 (s, 1H), 4.34 (bs, 2H), 3.99 (s, 3H), 3.77(bs, 2H), 3.34 (s, 3H); LC-MS (ESI) m/z 520 (M+H)⁺.

Example 230 Preparation of1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio],phenyl}urea

Example 230A: To a suspension of sodium hydride (422 mg, 17.6 mmol) inanhydrous tetrahydrofuran (100 mL) cooled to 0° C., 3-aminothiophenol(125 mg, 16.8 mmol) was added dropwise as a solution in tetrahydrofuran(5 mL). The mixture was stirred at 0° C. for 30 minutes.4-Chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline, previouslysynthesized, was added and the resulting mixture heated to 50° C.overnight. After removal of the solvent the residue was taken into ethylacetate/water, the organic layer separated and the aqueous phaseextracted twice. The organics were combined, dried (MgSO₄) andconcentrated under reduced pressure. The residue was triturated inmethanol to give3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline (2.8 g, 49%)as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.69 (s, 1H), 7.33 (d, 2H),7.16-7.10 (m, 1H), 6.81 (s, 1H), 6.75-6.67 (m, 2H), 5.35 (bs, 2H), 4.33(bs, 2H), 4.02 (s, 6H), 3.77 (bs, 2H); LC-MS (ESI) m/z 358 (M+H)⁺.

Example 230B: The title compound was prepared as described in Example162B, using phenyl5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate as describedin Example 162A (0.089 g, 0.3 mmol),3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline from theprevious step (0.107 g, 0.3 mmol), and 4-(dimethylamino)pyridine (0.03g) in THF (6 mL), to afford1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}ureaas solid (0.038 g, 23%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.71 (s, 1H), 9.02(s, 1H), 8.69 (s, 1H), 7.84 (m, 1H), 7.28-7.54 (m, 5H), 6.78 (s, 1H),4.72 (s, 2H), 4.56 (s, 2H), 4.33 (m, 2H), 3.99 (s, 3H), 3.77 (m, 2H),3.34 (s 3H), 1.29 (s, 3H); LC-MS (ESI) m/z 560 (M+H)⁺.

Example 231 Preparation of1-(3-fluoro-4-(trifluoromethyl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea

The procedure for Example 138B was used to react3-fluoro-4-(trifluoromethyl)phenylcarbamate as described in Example 150(138 mg, 0.46 mmol) with3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described inExample 231A (110 mg, 0.31 mmol). To this solution was addeddiisopropylethyl amine (80 μL, 0.46 mmol) and DMAP (4.0 mg, 0.03 mmol).The reaction was concentrated to dryness and triturated withdichloromethane to give 122 mg. ¹H (DMSO-d6) 9.43 (s, 1H), 9.15 (s, 1H),8.70 (s, 1H), 7.84 (s, 1H), 7.70 (m, 2H), 7.60 (m, 1H), 7.50 (m, 1H),7.40 (m, 4H), 4.34 (m, 2H), 4.00 (s, 3H), 3.78 (m, 2H), 3.38 (m, 3H).LCMS (ESI) m/z 563 (M+H)

Example 232 Preparation of1-(5-isopropylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea

Using the procedure described in Example 113C3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described inExample 231A (107 mg, 0.3 mmol) was reacted with phenyl5-isopropylisoxazol-3-ylcarbamate described in Example 133A (110 mg,0.45 mmol). The mixture was stirred at 50° C. overnight. Upon cooling toroom temperature, the product precipitated out of the solution. Thesolid was filtered off and washed with diethyl ether to give1-(5-isopropylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea(72.22 mg, 47%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s, 1H),9.02 (s, 1H), 8.69 (s, 1H), 7.84 (s, 1H), 7.53-7.28 (m, 5H), 6.51 (s,1H), 4.34 (bs, 2H), 4.00 (s, 3H), 3.76 (bs, 2H), 3.34 (s, 3H), 3.04-3.00(m, 1H), 1.23 (s, 6H); LC-MS (ESI) m/z 510 (M+H)⁺.

Example 233 Preparation of1-(3-methoxy-4-(trifluoromethyl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea

The procedure for Example 138B was used to react phenyl3-methoxy-4-(trifluoromethyl)phenylcarbamate described in Example 190B(144 mg, 0.46 mmol) with3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described inExample 231A (110 mg, 0.31 mmol). To this solution was addeddiisopropylethyl amine (80 μL, 0.46 mmol) and DMAP (4.0 mg, 0.03 mmol).The reaction was concentrated to dryness and purified by silica gelchromatography eluting with ethyl acetate/dichloromethane 0-50% over 75minutes. The main peak collected and concentrated, then triturated withdichloromethane to give a solid weighing 43 mg. ¹H (DMSO-d6) 9.19 (s,1H), 9.04 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.6-7.40 (m, 4H), 7.35(m, 2H), 7.25 (m, 1H), 7.00 (m, 1H), 4.34 (m, 2H), 4.00 (s, 3H), 3.84(s, 3H), 3.78 (m, 2H). LCMS (ESI) m/z 575 (M+H)

Example 234 Preparation of1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea

The procedure for Example 138B was used to react phenyl3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (86 mg,0.33 mmol) with3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described inExample 231A (97 mg, 0.27 mmol). To this solution was addeddiisopropylethyl amine (71 μL, 0.41 mmol) and DMAP (5.0 mg, 0.04 mmol).The reaction was concentrated to dryness and partitioned between waterand dichloromethane, and extracted twice. The combined extracts werewashed with brine, dried over magnesium sulfate, filtered andconcentrated. The oil was purified by silica gel chromatography elutingwith ethyl acetate/dichloromethane 12-70% over 18 column volumes. Theappropriate peak was concentrated to a white solid weighing 18 mg. ¹H(DMSO-d6) 10.42 (s, 1H), 9.11 (s, 1H), 8.69 (s, 1H), 7.84 (s, 1H), 7.55(m, 1H), 7.45 (m, 1H), 7.34 (m, 3H), 6.16 (s, 1H), 4.33 (m, 2H), 4.00(s, 3H), 3.76 (s, 2H), 1.70 (s, 3H), 1.63 (s, 3H). LCMS (ESI) m/z 528(M+H)

Example 235 Preparation of1-(5-cyclopentylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea

Using the procedure described in Example 113C compound3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described inExample 231A (114 mg, 0.32 mmol) was reacted with phenyl5-isopropylisoxazol-3-ylcarbamate described in Example 135A (130 mg,0.48 mmol). Upon addition of dietyl ether, the solid was filtered offand washed with diethyl ether to give1-(5-cyclopentylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea(91.12 mg, 53%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.52 (s,1H), 9.07 (s, 1H), 8.68 (s, 1H), 7.79 (s, 1H), 7.59-7.41 (m, 2H),7.41-7.24 (m, 3H), 6.50 (s, 1H), 4.39-4.24 (m, 2H), 4.00 (s, 3H),3.88-3.66 (m, 2H), 3.34 (s, 3H), 3.25-3.04 (m, 1H), 2.09-1.88 (m, 2H),1.75-1.48 (m, 6H); LC-MS (ESI) m/z 536 (M+H)⁺.

Example 236 Preparation of1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea

The procedure for Example 138B was used to react carbamate phenyl3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate described in Example 154A(151 mg, 0.45 mmol) with3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described inExample 231A (107 mg, 0.30 mmol). To this solution was addeddiisopropylethyl amine (80 μL, 0.45 mmol) and DMAP (4 mg, 0.03 mmol).After heating for 2 hours the reaction was concentrated to dryness. Theresulting solid was triturated with 1:1 dichloromethane/hexane and thesolid removed by filtration to give 26 mg. ¹H (DMSO-d6) 9.23 (s, 1H),8.68 (s, 1H), 8.47 (s, 1H), 7.79 (s, 1H), 7.55 (m, 4H), 7.40 (m, 5H),7.25 (s, 1H), 6.35 (s, 1H), 4.33 (m, 2H), 3.99 (s, 3H), 3.75 (m, 2H),3.34 (s, 3H), 1.25 (s, 9H); LCMS (ESI) m/z 599 (M+H).

Example 237 Preparation of ethyl2-[3-tert-butyl-5-(3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}ureido)-1H-pyrazol-1-yl]acetate

Using the procedure described in Example 159B, ethyl2-[3-tert-butyl-5-(phenoxycarbonylamino)-1H-pyrazol-1-yl]acetatedescribed in Example 166A (0.138 g, 0.4 mmol),3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described inExample 231A (0.143 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL)in THF (6 mL) at 50° C. for 7 hours, to afford ethyl2-[3-tert-butyl-5-(3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}ureido)-1H-pyrazol-1-yl]acetateas solid (0.071 g, 29%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.98 (br, 1H), 8.74(s, 1H), 8.60 (s, 1H), 7.83 (s, 1H), 7.34-7.52 (m, 4H), 7.26 (d, 1H),6.12 (s, 1H), 4.85 (s, 2H), 4.33 (m, 2H), 4.15 (q, 2H), 4.00 (s, 3H),3.77 (m, 2H), 3.34 (s, 3H), 1.20 (s and t, 12H); LC-MS (ESI) m/z 609(M+H)⁺.

Example 238 Preparation of1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}urea

Using the procedure described in Example 159B, phenyl3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamatedescribed in Example 167B (0.186 g, 0.5 mmol),3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described inExample 231A (0.143 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL)in THF (6 mL) at 50° C. for 6 hours, which was purified by silica gelchromatography with EtOAc/hexane as eluants and preparative HPLC (C₁₈column and 55-70% MeCN/H₂O with 0.05% AcOH) to afford1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}ureaas solid (0.072 g, 28%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H), 8.68(s, 1H), 8.56 (s, 1H), 7.80 (s, 1H), 7.56 (m, 4H), 7.33-7.47 (m, 5H),7.24 (d, 1H), 6.51 (s, 1H), 4.71 (m, 2H), 4.55 (m, 2H), 4.33 (m, 2H),3.99 (s, 3H), 3.77 (m, 2H), 3.34 (s, 3H), 1.31 (s, 3H); LC-MS (ESI) m/z635 (M+H)⁺.

Example 239 Preparation of1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea

Using the procedure described in Example 159B, using phenyl1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described inExample 164B (0.114 g, 0.4 mmol),3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described inExample 231A (0.143 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL)in THF (6 mL) at 50° C. for 3 hours, to afford1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]ureaas solid (0.033 g, 15%). ¹H NMR (300 MHz, CDCl₃) δ 9.4 (br, 1H), 8.75(s, 1H), 7.79 (m, 1H), 7.62 (d, 1H), 7.27-7.46 (m, 5H), 6.36 (s, 1H),4.34 (t, 2H), 4.04 (s, 3H), 3.90 (s and t, 5H), 3.49 (s, 3H); LC-MS(ESI) m/z 549 (M+H)⁺.

Example 240 Preparation of1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]-phenyl}-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea

Using the procedure described in Example 159B, phenyl1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate described inExample 165A (0.114 g, 0.4 mmol),3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described inExample 231A (0.143 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL)in THF (6 mL) at 50° C. for 3 hours, to afford1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]ureaas solid (0.015 g, 7%). ¹H NMR (300 MHz, CDCl₃) δ 9.45 (br, 1H), 8.76(s, 1H), 7.78 (m, 1H), 7.63 (d, 1H), 7.43 (t, 1H), 7.26-7.38 (m, 4H),6.32 (s, 1H), 4.34 (t, 2H), 4.04 (s, 3H), 3.89 (s and t, 5H), 3.49 (s,3H); LC-MS (ESI) m/z 549 (M+H)⁺.

Example 241 Preparation of1-[3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}urea

Using the procedure described in Example 159B, phenyl3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate described inExample 168B (0.115 g, 0.33 mmol),3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described inExample 231A (0.118 g, 0.33 mmol), and N,N-diisopropylethylamine (0.8mL) in THF (6 mL) at 50° C. for 5 hours, to afford1-[3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}ureaas solid (0.111 g, 54%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (br, 1H), 8.68(s, 1H), 8.54 (s, 1H), 7.79 (s, 1H), 7.54 (m, 4H), 7.37 (m, 5H), 7.25(d, 1H), 6.42 (s, 1H), 4.33 (m, 2H), 3.99 (s, 3H), 3.76 (m, 2H), 3.34(s, 3H), 3.25 (q, 2H), 1.46 (s, 6H), 1.04 (t, 3H); LC-MS (ESI) m/z 583(M−OEt)⁺.

Example 242 Preparation of1-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}urea

The title compound was prepared as described in Example 162B, usingphenyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamatedescribed in Example 171B (0.146 g, 0.4 mmol),3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described inExample 231A (0.143 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025g) in THF (6 mL), to afford1-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}ureaas solid (0.062 g, 25%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (s, 1H), 8.79(s, 1H), 8.68 (d, 1H), 7.78 (s, 1H), 7.68 (m, 2H), 7.45 (m, 4H), 7.37(s, 1H), 7.33 (s, 1H), 7.27 (d, 1H), 6.87 (s, 1H), 4.33 (m, 2H), 4.02(s, 3H), 3.76 (m, 2H), 3.34 (s, 3H); LC-MS (ESI) m/z 629 (M+H)⁺.

Example 243 Preparation of1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-[1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea

The title compound was prepared as described in Example 162B, usingphenyl 1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate describedin Example 172B (0.145 g, 0.4 mmol),3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described inExample 231A (0.143 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025g) in THF (6 mL), to afford1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-[1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]ureaas solid (0.177 g, 71%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 8.74(s, 1H), 8.68 (d, 1H), 7.78 (s, 1H), 7.45 (m, 6H), 7.37 (s, 1H), 7.33(s, 1H), 7.27 (d, 1H), 6.85 (s, 1H), 4.34 (m, 2H), 3.99 (s, 3H), 3.76(m, 2H), 3.35 (s, 3H), 2.41 (s, 3H); LC-MS (ESI) m/z 625 (M+H)⁺.

Example 244 Preparation of1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]urea

The title compound was prepared as described in Example 169C with phenyl1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamte described inExample 169B (0.115 g, 0.33 mmol) and the amine described in Example231A (0.118 g, 0.33 mmol), to afford1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]ureaas solid (0.096 g, 48%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.47 (s, 1H), 9.01(s, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.56 (m, 6H), 7.45 (t, 1H), 7.40(m, 2H), 7.28 (d, 1H), 7.14 (s, 1H), 4.35 (m, 2H), 4.00 (s, 3H), 3.77(m, 2H), 3.34 (s, 3H); LC-MS (ESI) m/z 611 (M+H)⁺.

Example 245 Preparation of1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(7-methoxy-6-(4,4-dioxo-3-thiomorpholinopropoxy)quinazolin-4-ylthio)phenyl)urea

Example 245A: In a round bottomed flask, sodium hydride (121 mg, 3.14mmol), a 60% dispersion in mineral oil, was suspended in 20 mL of dryTHF. To this suspension 3-aminothiophenol (394 mg, 3.14 mmol) was addedand the reaction stirred for 30 minutes. To this solution4-chloro-6-(3-chloropropoxy)-7-methoxyquinazoline (900 mg, 3.14 mmol)and the reaction stirred overnight. The reaction was quenched withwater, concentrated, and partitioned between water and ethyl acetate.After extracting twice, the extracts were combined, dried over magnesiumsulfate, filtered and concentrated to give3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)aniline as a yellowsolid and used without further purification. ¹H(DMSO-d6) 8.70 (s, 1H),7.34 (s, 1H), 7.15 (m, 1H), 6.80 (s, 1H), 6.75 (m, 2H), 4.28 (m, 2H),3.99 (s, 3H), 3.84 (m, 2H), 2.38 (m, 2H); LCMS (ESI) m/z 376 (M+H).

Example 245B: The procedure in Example 138B was used to react phenyl3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (60 mg,0.23 mmol) with the amine from the previous step (60 mg, 0.13 mmol). Tothis solution was added thiomorpholine dioxide (35 μL, 0.20 mmol) andDMAP (10 mg, 0.08 mmol). After heating for 2 hour the reaction wasconcentrated to dryness. The resulting solid was triturated with etherand the solid collected by vacuum filtration to give 88.5 mg. ¹H(DMSO-d6) 10.45 (s, 1H), 9.15 (s, 1H), 8.85 (s, 1H), 7.55 (m, 1H), 7.45(m, 1H), 7.35 (m, 2H), 6.19 (s, 1H), 5.33 (s, 2H), 4.25 (m, 2H), 3.95(s, 3H), 3.15 (m, 4H), 2.90 (m, 4H), 2.65 (m, 2H), 2.00 (t, 2H), 1.70(s, 3H), 1.60 (s, 1H). LCMS (ESI) m/z 645 (M+H).

Example 246 Preparation of1-(4-methoxy-3-(trifluoromethyl)phenyl)-3-(3-(7-methoxy-6-(3-(4,4-dioxothiomorpholino)propoxy)quinazolin-4-ylthio)phenyl)urea

Example 246A Step 1: Following the procedure for Example 138B3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)aniline described inExample 246A (150 mg, 0.40 mmol) was dissolved in 10 mL of dry THF. Tothis solution was added phenyl4-methoxy-3-(trifluoromethyl)phenylcarbamate described in Example 138A(150 mg, 0.48 mmol), diisopropyl ethyl amine (140 μL, 103 mg, 0.80mmol), and DMAP (10 mg). The solution was stirred overnight at roomtemperature, and then heated at 70 C for 3 hrs. The solution wasconcentrated to dryness and dissolved in a minimal volume ofdichloromethane and the product precipitated with hexane. The solid wascollected by filtration. LCMS (ESI) m/z 594 (M+H)

Example 246A Step 2: The above chloride was dissolved in 10 mL of dryacetone, to this solution sodium iodide (925 mg, 6.17 mmol) was addedand the solution heated at reflux overnight. The solution was thenconcentrated to dryness and triturated with dichloromethane. The solidsodium chloride was removed by filtration, and the filtrate concentratedto an oil. ¹H (DMSO-d6) 8.67 (s, 1H), 8.07 (s, 1H), 7.82 (s, 1H), 7.71(s, 1H), 7.51 (s, 1H), 7.40 (m, 3H), 7.24 (m, 4H), 6.81 (m, 2H), 4.30(m, 2H), 4.01 (s, 3H), 3.79 (m, 5H), 3.45 (m, 2H), 2.44 (m, 2H); LCMS(ESI) m/z 685 (M+H).

Example 246A Step 3: The crude oil was dissolved in 5 mL of dry DMF andthiomorpholine dioxide (55 mg, 0.4 mmol) was added and the reactionstirred at room temperature overnight. At the end of this time thereaction was diluted with methanol and purified by reversed phase HPLCusing a gradient of acetonitrile/water 40-70% over one hour. The majorpeak was collected and concentrated to a white solid weighing 26.7 mg.¹H (DMSO-d6) 9.0 (s, 1H), 8.90 (s, 1H), 8.70 (s, 1H), 7.85 (s, 2H), 7.55(m, 2H), 7.5 (m, 1H), 7.35 (s, 2H), 7.20 (m, 2H), 4.25 (m, 2H), 3.95 (m,2H), 3.85 (s, 2H), 3.15 (m, 2H), 2.85 (m, 2H), 2.60 (m, 2H), 2.0 (m,2H); LCMS (ESI) m/z 692 (M+H).

Example 247 Preparation of1-(3-(6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)-3-(3-tert-butylisoxazol-5-yl)urea

Example 247A: 3-Aminothiophenol (56 mg, 0.45 mmol) was treated withcesium carbonate (193 g, 0.59 mmol) in anhydrous tetrahydrofuran (22 mL)and the mixture stirred at room temperature for 30 minutes.4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (142 mg, 0.45 mmol) fromExample 12A was added and the mixture stirred at 60° C. overnight. Aftercooling to room temperature the mixture was diluted with chloroform,water and brine were added and the organic phase separated. The waterphase was extracted three times with chloroform, dried (MgSO₄) andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (dichloromethane/methanol 9:1) to afford3-(6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio)aniline (140 mg, 77%) asa solid. ¹H NMR (300 MHz, CDCl₃) δ 8.75 (s, 1H), 7.41 (s, 1H), 7.26 (t,2H), 6.99-6.94 (m, 2H), 6.74 (d, 1H), 4.30 (s, 4H), 3.99 (bs, 6H), 3.87(s, 6H); LC-MS (ESI) m/z 402 (M+H)⁺.

Example 247B: The title compound was prepared as described in Example113C by using compound3-(6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio)aniline (138 mg, 0.34mmol) and phenyl 3-tert-butylisoxazol-5-ylcarbamate described in Example132A (116 mg, 0.45 mmol) to give1-(3-(6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)-3-(3-tert-butylisoxazol-5-yl)urea(100 mg, 52%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.20 (s, 1H),9.05 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.46 (d, 1H), 7.45-7.38 (m,3H), 7.31 (d, 1H), 6.05 (s, 1H), 4.36-4.32 (m, 4H), 3.79-3.76 (m, 4H),3.37 (s, 6H), 1.24 (s, 9H); LC-MS (ESI) m/z 568 (M+H)⁺.

Example 248 Preparation of1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-ylthio)phenyl)urea

Example 248A: In a round bottomed flask 3-aminothiophenol (279 mg, 2.23mmol) was dissolved in 10 mL of dry THF. To this solution was addedsodium hydride, 60% suspension in mineral oil, (86 mg, 2.23 mmol) andthe reaction stirred for 30 minutes.4-chloro-7-(2-chloro-ethoxy)-6-methoxy-quinazoline (610 mg, 2.23 mmol)from Example 35A was added as a 10 mL solution in THF, and the reactionstirred overnight at room temperature. The solution was thenconcentrated to dryness, and partitioned between ethyl acetate andwater, and extracted with an additional portion of ethyl acetate. Theextracts were combined, dried with magnesium sulfate, filtered, andconcentrated to give3-(7-(2-chloroethoxy)-6-methoxyquinazolin-4-ylthio)aniline as a yellowsolid weighing 600 mg. ¹H NMR (300 MHz, DMSO-d₆) δ 8.70 (s, 1H), 7.47(d, 2H), 7.17 (m, 1H), 6.83 (s, 1H), 6.72 (m, 2H), 4.51 (m, 2H), 4.05(m, 3H), 3.89 (s, 3H), 3.51 (bs, 2H); LC-MS (ESI) m/z 362 (M+H)⁺.

Example 248B: The procedure for Example 138B was used to react phenyl3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (54 mg,0.20 mmol) with the aniline from the previous step (75 mg, 0.18 mmol).To this solution was added diisopropylethyl amine (47 μL, 0.27 mmol) andDMAP (2.0 mg, 0.02 mmol). The reaction was concentrated to dryness andpartitioned between water and dichloromethane, and extracted twice. Thecombined extracts were washed with brine, dried over magnesium sulfate,filtered and concentrated. The oil was purified by silica gelchromatography (eluting with methanol/dichloromethane 1-8%) to affordthe title compound as a white solid (31 mg, 30% yield). ¹H NMR (300 MHz,DMSO-d₆) δ 10.42 (s, 1H), 9.11 (s, 1H), 8.69 (s, 1H), 7.6-7.2 (m, 6H),6.16 (s, 1H), 4.33 (m, 2H), 4.00 (s, 3H), 3.60 (m, 7H), 2.80 (m, 2H),1.70 (s, 3H), 1.63 (s, 3H). LC-MS (ESI) m/z 583 (M+H)⁺.

Example 249 Preparation of1-(4-methoxy-3-(trifluoromethyl)phenyl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-ylthio)phenyl)urea

The procedure for Example 138B was used to react phenyl4-methoxy-3-(trifluoromethyl)phenylcarbamate described in Example 138A(62 mg, 0.20 mmol) with3-(7-(2-chloroethoxy)-6-methoxyquinazolin-4-ylthio)aniline described inExample 249A (75 mg, 0.18 mmol). To this solution was addeddiisopropylethyl amine (47 μL, 0.27 mmol) and DMAP (2.0 mg, 0.02 mmol).The reaction was concentrated to dryness and partitioned between waterand dichloromethane, and extracted twice. The combined extracts werewashed with brine, dried over magnesium sulfate, filtered andconcentrated. The oil was purified by silica gel chromatography elutingwith methanol/dichloromethane 1-8% over 18 column volumes. Theappropriate peak was concentrated to a white solid (18.6 mg, 15%). ¹H(DMSO-d6) 9.3 (m, 2H), 8.7 (s, 1H), 7.85 (s, 2H), 7.6 (m, 3H), 7.5-7.2(m, 5H) 4.4 (m, 3H), 4.0 (m, 4H), 3.8 (m, 6H), 2.8 (m, 2H). LCMS (ESI)m/z 630 (M+H)

Example 250 Preparation of1-(4-methoxy-3-(trifluoromethyl)phenyl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)urea

Example 250A Step 1: To morpholine (5 mL) was added7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ol (600 mg, 2.36 mmol) fromExample 35A and the mixture heated at 100° C. for 4 hours. After coolingto room temperature, the mixture was diluted with DCM and filtered. Theresulting solid was washed with MeOH and H₂O to give4-hydroxy-6-methoxy-7-(2-morpholinoethoxy)quinazoline (328 mg, 1.07mmol, 46%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.08 (br s, 1H), 7.98 (s, 1H),7.44 (s, 1H), 7.17 (s, 1H), 4.23 (t, 2H), 3.87 (s, 3H), 3.58 (t, 4H),3.41-3.32 (m, 4H), 2.75 (t, 2H); LC-MS (ESI) m/z 306 (M+H)⁺.

Example 250A Step 2: The procedure described in Example 4A Step 2 butusing 4-hydroxy-6-methoxy-7-(2-morpholinoethoxy)quinazoline (325 mg,1.07 mmol) afforded4-(2-(4-chloro-6-methoxyquinazolin-7-yloxy)ethyl)morpholine (196 mg,0.61 mmol, 57%). LC-MS (ESI) m/z 324 (M+H)⁺.

Example 250A Step 3: 3-Aminophenol (338 mg, 3.09 mmol) was treated withcesium carbonate (2 g, 6.2 mmol) in anhydrous isopropanol (10 mL) andthe mixture stirred at room temperature for 30 minutes.4-(2-(4-chloro-6-methoxyquinazolin-7-yloxy)ethyl)morpholine from theprevious step (1 g, 3.09 mmol) was added and the mixture stirred at 80°C. for 2 h. Cesium carbonate was filtered off, washed with isopropanoland the filtrate concentrated under reduced pressure. The residue waspurified by silica gel chromatography (dichloromethane/methanol 9:1) toafford 3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)aniline(236 mg, 22%) as a brownish solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.54 (s,1H), 7.51 (s, 1H), 7.41 (s, 1H), 7.09 (t, 1H), 6.50-6.37 (m, 3H), 5.30(bs, 2H), 4.34-4.30 (m, 2H), 3.91 (s, 3H), 3.60 (s, 4H), 2.82-2.70 (m,2H) 2.59-2.42 (m, 4H); LC-MS (ESI) m/z 397 (M+H)⁺.

Example 250B: Using the procedure described in Example 230B3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)aniline (90 mg,0.23 mmol) was reacted with phenyl4-methoxy-3-(trifluoromethyl)phenylcarbamate described in Example 138A(99 mg, 0.32 mmol) and 4-(dimethylamino)pyridine (28 mg, 0.23 mmol) togive1-(4-methoxy-3-(trifluoromethyl)phenyl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)urea(38.72 mg, 27%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.92 (bs,1H), 8.85 (bs, 1H), 8.56 (s, 1H), 7.60-7.51 (m, 3H), 7.43-7.35 (m, 2H),7.26-7.19 (m, 2H), 6.92 (d, 1H), 4.33 (bs, 2H), 3.99 (s, 3H), 3.84 (s,2H), 3.61 (s, 4H), 2.90-2.69 (m, 2H), 2.65-2.55 (m, 2H); LC-MS (ESI) m/z614 (M+H)⁺.

Example 251 Preparation of1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)urea

Using the procedure described in Example 229B by using3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)aniline describedin Example 251A Step 3 (146 mg, 0.37 mmol) was reacted with phenyl3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (117 mg,0.44 mmol) and 4-(dimethylamino)pyridine (45 mg, 0.37 mmol) to give1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)urea(101.6 mg, 49%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.41 (s, 1H),9.11 (s, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.44-7.40 (m, 2H), 7.32 (d,1H), 7.00 (d, 1H), 6.15 (s, 1H), 4.35-4.33 (m, 2H), 3.98 (s, 3H),3.62-3.60 (m, 4H), 2.85-2.70 (m, 2H), 2.52-2.50 (m, 4H), 1.70 (s, 3H),1.63 (s, 3H); LC-MS (ESI) m/z 567 (M+H)⁺.

Example 252 Preparation of1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 252A Step 1: 1-tert-butyl-1H-pyrazol-4-amine was synthesizedaccording to the procedure described in Bull. Chem. Soc. Jpn. 1996, 69,1997-2002.

Example 252A Step 2: To a solution containing1-tert-butyl-1H-pyrazol-4-amine (0.995 g, 7.16 mmol) in THF (20 mL),phenylchloroformate (1.00 mL, 8.02 mmol) and K₂CO₃ (1.32 g, 9.52 mmol)were added at room temperature. After stirring overnight, the mixturewas filtered and the solid washed with THF. The filtrate wasconcentrated to dryness and the residue was dissolved in DCM and theorganic solution was washed with brine and dried over MgSO₄ to yieldphenyl 1-tert-butyl-1H-pyrazol-4-ylcarbamate as a solid (1.65 g, 89%).¹H NMR (300 MHz, CDCl₃) δ 7.85 (1H, s), 7.30 (6H, m), 1.60 (9H, s).

Example 252A Step 3: To a solution of1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(3-hydroxyphenyl)urea (0.782 g, 3.02mmol) in anhydrous THF (10 mL), 3-aminophenol was added at roomtemperature. The mixture was stirred at 120 C for 2 h in a sealed tube.The reaction mixture was concentrated to dryness and the residue wasdissolved in ethyl acetate. The organic solution was washed with water,brine and dried over MgSO₄. The solvent was evaporated and the cruderesidue was purified on silica gel column, using a mixture of DCM/MeOHas mobile phase to yield1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(3-hydroxyphenyl)urea (0.169 g, 20%).¹HNMR (dmso-d6): δ 9.25 (1H, s), 8.48 (1H, s), 8.20 (1H, s), 7.80 (1H,s), 7.39 (1H, s), 7.02 (2H, m), 6.77 (1H, d), 6.35 (1H, d), 1.49 (9H,s).

Example 252B: To a solution of1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(3-hydroxyphenyl)urea (0.10 g, 0.62mmol) in anhydrous THF (8 mL), Cs₂CO₃ (0.403 g, 1.23 mmol) were added.After stirring the heterogeneous mixture for 1 h,4-chloro-6,7-dimethoxyquinazoline (0.138 g, 0.62 mmol) was added at roomtemperature. The reaction mixture was stirred at 55 C overnight. Themixture was filtered and the filtrate was concentrated to dryness. Thecrude was purified on HPLC. The titled compound was obtained as a whitesolid. Yield: 0.122 mg (42%). ¹HNMR (dmso-d6): δ 8.86 (1H, s), 8.55 (1H,s), 8.40 (1H, s), 7.80 (1H, s), 7.59 (1H, s), 7.54 (1H, s), 7.35 (3H,m), 7.23 (1H, d), 6.88 (1H, d), 3.98 (6H, s), 1.50 (9H, s). LC/MS: M+1:463.

Example 253 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylsulfinyl)phenyl)urea

To a stirring solution of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(120 mg, 0.25 mmol) from Example 46 in dichloromethane (2.5 mL) wasadded 3-chloroperoxybenzoic acid (56 mg, 77% max, 0.25 mmol). Thereaction was quenched after 5 minutes with sat. NaHCO₃(aq), extractedwith EtOAc, dried over MgSO₄, filtered, and concentrated in vacuo. Thecrude product was purified by column chromatography (25-100%EtOAc/hexanes) then repurified (12-100% EtOAc/hexanes) to give1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylsulfinyl)phenyl)urea(21 mg, 0.42 mmol, 17%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s, 1H),9.16-9.12 (m, 2H), 8.33-8.28 (m, 2H), 7.49-7.34 (m, 4H), 6.50 (s, 1H),4.03 (s, 3H), 3.99 (s, 3H), 1.30 (s, 9H); LC-MS (ESI) m/z 496 (M+H)⁺.

Example 254 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea

According to the procedure described in Example 113C,3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (104 mg, 0.35 mmol) andphenyl 3-(trifluoromethyl)isoxazol-5-ylcarbamate described in Example229A (124 mg, 0.45 mmol) were reacted to give1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea(9.23 mg, 6%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.90 (bs,1H), 9.30 (bs, 1H), 8.59 (bs, 1H), 7.8-7.20 (m, 5H), 7.06 (bs, 1H), 6.50(s, 1H), 4.09 (s, 6H); LC-MS (ESI) m/z 476 (M+H)⁺.

Example 255 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(1-hydroxy-2-methylpropan-2-yl)isoxazol-5-yl)urea

Example 255A Step 1: 5-Hydroxy-4,4-dimethyl-3-oxopentanenitrile (1equivalent) and sodium hydroxide (2 equivalents) with a reaction pH of10-13 was reacted in a similar manner to that described in Example 122AStep 2, to afford 2-(5-aminoisoxazol-3-yl)-2-methylpropan-1-ol as acolorless solid which can be used in the next step without furtherpurification. ¹H NMR (300 MHz, CDCl₃) δ 5.04 (s, 1H), 4.47 (brs, 2H),3.65 (s, 2H), 2.50 (brs, 1H), 1.28 (s, 6H); LC-MS (ESI) m/z 157 (M+H)⁺.

Example 255A Step 2: 245-Aaminoisoxazol-3-yl)-2-methylpropan-1-ol (100mg, 0.60 mmol) was reacted according to the procedure described inExample 122A Step 3 to afford phenyl3-(1-hydroxy-2-methylpropan-2-yl)isoxazol-5-ylcarbamate as a colorlesssolid (77 mg, 46%) that was not purified further.

Example 255B: 3-(6,7-Dimethoxyquinazolin-4-yloxy)aniline (40 mg, 0.13mmol) and the carbamate from the previous step (50 mg, 0.18 mmol) werereacted according to the procedure described in Example 122B.Purification via preparative TLC eluting with 10% methanol indichloromethane afforded1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(1-hydroxy-2-methylpropan-2-yl)isoxazol-5-yl)ureaas a pinkish solid (38 mg, 59%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.21 (brs,1H), 9.08 (brs, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.38-7.40 (m, 2H), 7.30(m, 1H), 6.99 (m, 1H), 6.02 (s, 1H), 4.80 (brs, 1H), 3.98-4.00 (2×s,6H), 3.39 (s, 2H), 1.16 (s, 6H); LC-MS (ESI) m/z 480 (M+H)⁺.

Example 256 Preparation of1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{7-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-urea

To a solution of1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea(described in Example 27B, 235 mg, 0.446 mmol) in DMF (3 mL) was addedthiomorpholine 1,1-dioxide (181 mg, 1.338 mmol) followed by diisopropylethylamine (0.233 mL, 1.338 mmol) and tetrabutyl ammonium iodide (164mg, 0.446 mmol). The reaction mixture was heated at 60° C. for 4 days.Formation of the product was determined by LCMS. The crude reactionmixture was purified by preparative HPLC (phenylhexyl reverse phasecolumn eluted with gradient of solvent A=0.05% HOAc/H₂O and solventB=0.05% HOAc/CH₃CN) to afford1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{7-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-ureaas a white solid (87 mg, 31%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.80-9.35(brs, 2H), 8.52 (s, 1H), 7.55 (d, 2H), 7.35 (m, 3H), 7.25 (d, 1H), 6.92(d, 1H), 6.45 (s, 1H), 4.25 (m, 2H), 3.95 (s, 3H), 3.10 (s, 4H), 2.80(s, 4H), 2.60 (s, 2H), 1.95 (s, 1H), 1.20 (s, 9H); LC-MS (ESI) m/z 625(M+H)⁺.

Example 257 Preparation of1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)urea

Example 257A: 3-(2-fluoropropan-2-yl)isoxazol-5-amine (11.26 g, 78.19mmol) described in Example 42A in THF (300 mL) was treated withpotassium carbonate (21.58 g, 156 mmol) and p-chlorophenyl chloroformate(14.94 g, 78.19 mmol). After stirring at rt for 1 h, additionalp-chlorophenyl chloroformate (7.5 g, 39.26 mmol) was introduced, and thereaction mixture was stirred at rt overnight. The mixture was filteredthrough a celite pad, washed with ethyl acetate and concentrated todryness. The residue was taken into ethyl acetate, washed with brine,and the organics dried (MgSO₄) and concentrated. The residue waspurified by silica gel chromatography (eluting with 10 to 50% ethylacetate in hexanes) to give 4-chlorophenyl3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate (16.51 g, 71%) as a creamsolid. ¹H NMR (300 MHz, CDCl₃) δ 7.87 (brs, 1H), 7.36-7.41 (m, 2H),7.13-7.17 (m, 2H), 6.27 (s, 1H), 1.74 (d, J=21 Hz, 6H); LC-MS (ESI) m/z299 (M+H)⁺.

Example 257B: To a stirred solution of4-(3-aminophenoxy)-6-methoxyquinazolin-7-ol (200 mg, 0.71 mmol)(prepared as described in example 95A, steps 1 through 3) in anhydrousDMF (6 mL), was added 4-chlorophenyl3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate (212 mg, 0.71 mmol) andthe mixture was heated to 60° C. for 2.5 h. Concentration in vacuofollowed by purification via preparative reverse phase HPLC (eluted witha gradient of solvent B=0.05% HOAc/CH₃CN and solvent A=0.05% HOAc/H₂O),afforded1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)urea(41 mg, 13%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.64(brs, 1H), 9.13 (brs, 1H), 8.48 (s, 1H), 7.55-7.56 (m, 2H), 7.41 (dd,J=8.1, 8.1 Hz, 1H), 7.32 (m, 1H), 7.23 (s, 1H), 6.98 (m, 1H), 6.15 (s,1H), 3.99 (s, 3H), 1.66 (d, J=22 Hz, 6H); LC-MS (ESI) m/z 454 (M+H)⁺.

Example 258 Preparation of1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)urea

To a stirred solution of 4-(3-aminophenoxy)-7-methoxyquinazolin-6-ol(200 mg, 0.710 mmol) (prepared as described in example 107A, steps 1through 7) in anhydrous DMF (6 mL), was added 4-chlorophenyl3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate described in Example 257A(317 mg, 1.07 mmol) and the mixture was heated to 60° C. for 3 h.Concentration in vacuo followed by trituration of the resulting solidwith methanol afforded, after filtration and drying,1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)urea(162 mg, 50%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.40(s, 1H), 10.30 (s, 1H), 9.08 (s, 1H), 8.50 (s, 1H), 7.53 (dd, J=2.1, 2.1Hz, 1H), 7.50 (s, 1H), 7.37-7.44 (m, 2H), 7.32 (dd, J=8.4, 1.8 Hz, 1H),6.97 (dd, J=8.4, 1.8 Hz, 1H), 6.15 (s, 1H), 4.00 (s, 3H), 1.66 (d, J=22Hz, 6H); LC-MS (ESI) m/z 454 (M+H)⁺.

Example 259 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea

Example 259A Step 1: Reaction was carried out in two separate batches,employing 5 g of 3,3,3-trifluoro-2,2-dimethylpropionic acid in eachbatch. To a stirred solution of 3,3,3-trifluoro-2,2-dimethylpropionicacid (5 g, 32 mmol) in anhydrous dichloromethane (20 mL) at 0° C. (underan argon atmosphere), was added dropwise a solution of(trimethylsilyl)diazomethane (18 mL of a 2M solution in diethyl ether,35 mmol) (gas evolution observed). The resulting yellow solution wasallowed to warm to rt and stirred for a further 48 h. An additional 5 mLof 2M (trimethylsilyl)diazomethane solution (10 mmol) was added, andstirring continued for a further 5 h whereupon a further 6 mL of 2 M(trimethylsilyl)diazomethane solution (12 mmol) was added. Afterstirring for a further 15 h, the reaction mixture was concentrated invacuo (keeping bath temperature below 30° C.). The resulting oil wasredissolved in diethyl ether (200 mL), washed with saturated sodiumhydrogencarbonate solution (100 mL), separated, and dried over MgSO₄.Filtration followed by concentration in vacuo (keeping bath temperaturebelow 30° C.) gave crude product. Crude product from both batches werecombined to afford crude methyl 3,3,3-trifluoro-2,2-dimethylpropanoate(7.69 g) as a yellow oil which was taken on without furtherpurification. ¹H NMR (300 MHz, CDCl₃) δ 3.86 (s, 3H), 1.40 (s, 6H).

Example 259A Step 2: Reaction was carried out in two separate batches,employing 3.85 g of methyl 3,3,3-trifluoro-2,2-dimethylpropanoate ineach batch. To a stirred refluxing suspension of sodium hydride (1.41 gof a 60% dispersion in mineral oil, 35 mmol) in dry THF (30 mL) (underan argon atmosphere) was added a mixture of crude methyl3,3,3-trifluoro-2,2-dimethylpropanoate (3.85 g) and dry acetonitrile(1.85 mL, 35 mmol), dropwise over the course of 45 mins. The resultingpale yellow suspension was heated at 70° C. for a further 15 h. Aftercooling to rt, both reaction batches were combined whereupon the solventwas removed in vacuo. The resulting orange foam was redissolved in water(200 mL) and washed with diethyl ether (2×200 mL), to remove residualmineral oil. The aqueous layer was separated, acidified to pH 2 withaqueous 2N hydrochloric acid and extracted with diethyl ether (3×200mL). The combined ether layers were dried over MgSO₄, filtered, thenconcentrated under reduced pressure to afford5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (4.27g, 37% from 3,3,3-trifluoro-2,2-dimethylpropionic acid) which was usedin the next step without further purification. ¹H NMR (300 MHz, CDCl₃) δ3.77 (s, 2H), 1.43 (s, 6H).

Example 259A Step 3: A mixture of5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (3 g, 16.76 mmol),hydroxylamine sulfate (3.30 g, 20.11 mmol) and sodium hydrogencarbonate(3.52 g, 41.90 mmol) in a mixture of 10% methanol in water (60 mL), washeated at 65° C. for 15 h. After cooling to rt, a further 30 mL of 10%methanol in water was added, and the mixture was divided into 9×10 mLbatches. Each batch was adjusted to pH 1 with concentrated hydrochloricacid and each placed into a 20 mL volume microwave vial fitted with astirrer bar. After sealing, each batch was placed in a Biotage MicrowaveSynthesizer and heated (with stirring) at 140° C. for 5 min (maximuminternal pressure attained was 7 bar). Each batch was cooled andneutralized with saturated aqueous sodium hydrogencarbonate solution.All processed batches were combined and concentrated in vacuo and theaqueous solution extracted with 10% isopropanol in chloroform (3×150mL). The combined organic layers were washed with brine (200 mL),separated, dried over MgSO₄ and filtered. Concentration in vacuoafforded 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (2.34g, 71%) as a light yellow solid which taken on without furtherpurification. ¹H NMR (300 MHz, CDCl₃) δ 5.80 (s, 1H), 3.98 (brs, 2H),1.53 (s, 6H); LC-MS (ESI) m/z 195 (M+H)⁺.

Example 259A Step 4:5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (123 mg, 0.63mmol) in THF (2 mL) was treated with potassium carbonate (113 mg, 0.819mmol) and p-chlorophenyl chloroformate (180 mg, 0.95 mmol). The reactionmixture was stirred at rt overnight. The mixture was filtered through acelite pad, washed with ethyl acetate and concentrated to dryness. Theresidue was taken into ethyl acetate, washed with brine, and theorganics dried (MgSO₄) and concentrated. The residue was purified bysilica gel chromatography (hexane/ethyl acetate 8:2) to give4-chlorophenyl5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (85 mg,39%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.83 (brs, 1H), 7.38(d, J=9 Hz, 2H), 7.15 (d, J=9 Hz, 2H), 6.82 (s, 1H), 1.59 (s, 6H); LC-MS(ESI) m/z 349 (M+H)⁺.

Example 259B: To a stirred solution of3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (36 mg, 0.122 mmol) describedin Example 113A in anhydrous THF (0.5 mL), was added 4-chlorophenyl5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate from theprevious step (85 mg, 0.244 mmol) and 4-(dimethylamino)pyridine (7.3 mg,0.06 mmol). The mixture was stirred at rt for 6 h. Concentration invacuo followed by purification by silica gel chromatography(dichloromethane/methanol 9:1) and trituration of the resulting solidwith diethyl ether afforded, after filtration and drying,1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea(22.8 mg, 18%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.76(s, 1H), 9.04 (s, 1H), 8.56 (s, 1H), 7.56-7.59 (m, 2H), 7.38-7.44 (m,2H), 7.27 (m, 1H), 6.99 (m, 1H), 6.88 (s, 1H), 4.00 (s, 6H), 1.54 (s,6H); LC-MS (ESI) m/z 518 (M+H)⁺.

Example 260 Preparation of1-(3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea

Example 260A: (Preparation of phenyl5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate): To astirred mixture of5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine prepared asdescribed in Example 259A (2.34 g, 12.06 mmol) and potassium carbonate(5 g, 36 mmol) in dry dichloromethane (50 mL) at 0° C., was added asolution of phenyl chloroformate (2.83 g, 18 mmol) in anhydrousdichloromethane (5 mL). The reaction mixture was warmed to roomtemperature and stirred for a further 15 h, then additional phenylchloroformate (1 g, 6.3 mmol) was added and stirring was continued for afurther 3 h. The reaction mixture was partitioned between water (200 mL)and dichloromethane (500 mL). The organic layer was separated, washedwith brine (100 mL), dried over MgSO₄, and then concentrated underreduced pressure to give a yellow oil. Purification via silica gel flashchromatography (eluting with 5% to 50% ethyl acetate in hexanes)afforded phenyl5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (2.63 g,69%) as a colorless solid. ¹H NMR (300 MHz, CDCl₃) δ 8.16 (brs, 1H),7.38-7.43 (m, 2H), 7.17-7.29 (m, 3H), 6.85 (s, 1H), 1.57 (s, 6H); LC-MS(ESI) m/z 315 (M+H)⁺.

Example 260B (Preparation of3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)aniline): To a stirredsuspension of cesium carbonate (3.60 g, 11.06 mmol) in THF (50 mL) wasadded 3-aminophenol (0.91 g, 8.38 mmol). After stirring for 30 minutesat rt, 4-chloro-6-ethoxy-7-methoxyquinazoline described in Example 11A(2.00 g, 8.38 mmol) was added and the reaction mixture was heated at 50°C. for 15 h. The reaction mixture was cooled to rt and diluted withethyl acetate. The solution was washed with aqueous 1 M NaOH solution,then brine, and dried over MgSO₄. Filtration and concentrated underreduced pressure, gave a solid that was triturated with ethyl acetate.Filtration and drying afforded3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)aniline (1.30 g, 50%) as a creamsolid, which did not require further purification. ¹H NMR (400 MHz,DMSO-d₆) δ 8.54 (s, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 7.08 (dd, J=8, 8Hz, 1H), 6.36-6.49 (m, 3H), 5.30 (brs, 2H), 4.21 (q, J=7 Hz, 2H), 3.98(s, 3H), 1.41 (t, J=7 Hz, 3H); LC-MS (ESI) m/z 312 (M+H)⁺.

Example 260C: To a stirred solution of3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)aniline (100 mg, 0.322 mmol) andphenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate(151 mg, 0.482 mmol) in anhydrous THF (5 mL), was added4-(dimethylamino)pyridine (6 mg, 0.0492 mmol) and the mixture wasstirred at rt for 15 h. Concentration in vacuo followed by purificationvia silica gel column chromatography (eluted with a gradient of 20%ethyl acetate in hexanes to 100% ethyl acetate), afforded1-(3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea(48 mg, 28%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.74(brs, 1H), 9.01 (s, 1H), 8.55 (s, 1H), 7.54-7.59 (m, 2H), 7.37-7.43 (m,2H), 7.26 (m, 1H), 6.98 (m, 1H), 6.87 (s, 1H), 4.24 (q, J=7 Hz, 2H),4.00 (s, 3H), 1.53 (s, 6H), 1.43 (t, J=7 Hz, 3H); LC-MS (ESI) m/z 532(M+H)⁺.

Example 261 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea

To a stirred solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)anilinedescribed in Example 115B (144 mg, 0.46 mmol) in anhydrous THF (5.6 mL),was added 4-chlorophenyl5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate describedin Example 259A (161 mg, 0.46 mmol) and 4-(dimethylamino)pyridine (31mg, 0.25 mmol). The mixture was stirred at rt for 15 h. To thesuspension was added diethyl ether. Sonication and filtration afforded1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea(134 mg, 55%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.77 (s,1H), 9.04 (s, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.28-7.54 (m, 5H), 6.89(s, 1H), 3.99 (s, 6H), 1.54 (s, 6H); LC-MS (ESI) m/z 534 (M+H)⁺.

Example 262 Preparation of1-(3-(6-ethoxy-7-methoxyquinazolin-4-ylthio)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea

Example 262A: To a stirred suspension of cesium carbonate (3.60 g, 11.06mmol) in THF (60 mL) was added 3-aminobenzenethiol (1.00 g, 7.99 mmol).After stirring for 30 minutes at rt,4-chloro-6-ethoxy-7-methoxyquinazoline described in Example 11A (1.91 g,7.99 mmol) was added and the reaction mixture was heated at rt for 15 h.The reaction mixture was cooled to rt and concentrated under reducedpressure to give a solid. Purification by silica gel columnchromatography (eluting with 2% methanol in dichloromethane) afforded3-(6-ethoxy-7-methoxyquinazolin-4-ylthio)aniline (1.20 g, 46%) as acream solid, which did not require further purification. ¹H NMR (400MHz, DMSO-d₆) δ 8.69 (s, 1H), 7.33 (s, 1H), 7.30 (s, 1H), 7.12 (dd, J=8,8 Hz, 1H), 6.79 (s, 1H), 6.66-6.73 (m, 2H), 5.33 (brs, 2H), 4.21 (q, J=7Hz, 2H), 3.98 (s, 3H), 1.43 (t, J=7 Hz, 3H); LC-MS (ESI) m/z 328 (M+H)⁺.

Example 262B: To a stirred solution of3-(6-ethoxy-7-methoxyquinazolin-4-ylthio)aniline (100 mg, 0.305 mmol)and phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamatedescribed in Example 260A (144 mg, 0.458 mmol) in anhydrous THF (5 mL),was added 4-(dimethylamino)pyridine (6 mg, 0.0492 mmol) and the mixturewas stirred at rt for 15 h. Concentration in vacuo followed bypurification via silica gel column chromatography (eluted with agradient of 20% ethyl acetate in hexanes to 100% ethyl acetate),afforded1-(3-(6-ethoxy-7-methoxyquinazolin-4-ylthio)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea(35 mg, 21%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.74(brs, 1H), 9.02 (s, 1H), 8.69 (s, 1H), 7.85 (m, 1H), 7.28-7.51 (m, 5H),6.88 (s, 1H), 4.23 (q, J=7 Hz, 2H), 3.99 (s, 3H), 1.54 (s, 6H), 1.45 (t,J=7 Hz, 3H); LC-MS (ESI) m/z 548 (M+H)⁺.

Example 263 Preparation of1-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea

To a stirred solution of 4-(3-aminophenoxy)-6-methoxyquinazolin-7-ol(100 mg, 0.35 mmol) prepared as described in example 95A in anhydrousDMF (3 mL), was added phenyl5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate describedin Example 260A (111 mg, 0.35 mmol) and the mixture was heated to 60° C.for 2 h. Additional phenyl5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (50 mg,0.16 mmol) was added and heating was continued for a further 72 h.Concentration in vacuo followed by purification via preparative reversephase HPLC (eluted with a gradient of solvent B=0.05% HOAc/CH₃CN andsolvent A=0.05% HOAc/H₂O), afforded1-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea(40 mg, 23%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.93(brs, 1H), 9.83 (s, 1H), 9.11 (s, 1H), 8.47 (s, 1H), 7.56 (dd, J=2.1,2.1 Hz, 1H), 7.53 (s, 1H), 7.40 (dd, J=8.1, 8.1 Hz, 1H), 7.26 (dd,J=8.1, 8.1 Hz, 1H), 7.21 (s, 1H), 6.96 (m, 1H), 6.88 (s, 1H), 3.98 (s,3H), 1.54 (s, 6H); LC-MS (ESI) m/z 504 (M+H)⁺.

Example 264 Preparation of1-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea

To a stirred solution of 4-(3-aminophenoxy)-7-methoxyquinazolin-6-ol (70mg, 0.247 mmol) described in Example 107A in anhydrous DMF (3 mL), wasadded phenyl5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate describedin Example 260A (90 mg, 0.287 mmol) and the mixture was heated to 60° C.for 15 h. Concentration in vacuo followed by trituration of theresulting solid with methanol afforded, after filtration and drying,1-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea(73 mg, 59%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.30 (s,1H), 9.75 (s, 1H), 9.01 (s, 1H), 8.49 (s, 1H), 7.55 (dd, J=2.1, 2.1 Hz,1H), 7.50 (s, 1H), 7.37-7.43 (m, 2H), 7.27 (dd, J=9, 1.2 Hz, 1H), 6.97(dd, J=8.1, 2.1 Hz, 1H), 6.88 (s, 1H), 4.00 (s, 3H), 1.54 (s, 6H); LC-MS(ESI) m/z 504 (M+H)⁺.

Example 265 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea

Example 265A Step 1: A solution of 2-fluoro-3-methoxybenzoic acid (5.00g, 29.39 mmol) and diisopropylethylamine (4.56 g, 35.27 mmol) in amixture of anhydrous toluene (25 mL) and anhydrous tert-butanol (25 mL)was stirred over activated 4 Å molecular sieves (4 g) for 1 h. Diphenylphosphoryl azide (9.71 g, 35.27 mmol) was added and the mixture washeated at reflux for 15 h. The reaction mixture was cooled and filtered.To the filtrate was added ethyl acetate (200 mL) and the solution waswashed with water (2×100 mL) and brine (100 mL). The organic phase wasseparated and dried over MgSO₄. Filtration followed by concentrationunder reduced pressure gave crude tert-butyl2-fluoro-3-methoxyphenylcarbamate. The crude product was dissolved in asolution of 6M HCl in ethyl acetate (20 mL, 0.12 mol) and the mixturestirred at rt for 2 h. The resulting precipitate was filtered and dried.The solid was taken up in a saturated aqueous solution of sodiumhydrogen carbonate (50 mL) and the mixture extracted withdichloromethane (2×100 mL). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated under reduced pressure to afford2-fluoro-3-methoxyaniline (3.00 g, 72%) as brown oil, which was taken onwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 6.80-7.02 (m,3H), 3.82 (s, 3H); LC-MS (ESI) m/z 142 (M+H)⁺.

Example 265A Step 2: To a stirred solution of 2-fluoro-3-methoxyaniline(3.0 g, 21.26 mmol) in dichloromethane (80 mL), at 0° C., was added a4.0 M solution of boron tribromide in dichloromethane (10.63 mL, 42.52mmol). The reaction mixture was allowed to warm to rt and stirring wascontinued for a further 15 h. The reaction mixture was quenched via theaddition of methanol. After concentration under reduced pressure, theresidue was taken up in water, basified with saturated sodium hydrogencarbonate solution, and extracted with ethyl acetate. The combined ethylacetate layers were washed with brine, dried over MgSO₄, andconcentrated under reduced pressure to afford 3-amino-2-fluorophenol(2.70 g, 100%) as a brown solid which was taken on without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 9.36 (brs, 1H), 6.62 (dd, J=8,8 Hz, 1H), 6.12-6.23 (m, 2H), 5.14 (brs, 2H); LC-MS (ESI) m/z 128(M+H)⁺.

Example 265A Step 3: To a stirred slurry of cesium carbonate (10.25 g,31.47 mmol) in a 9:1 mixture of THF/DMF (100 mL) at rt, was added3-amino-2-fluorophenol (2.00 g, 15.74 mmol) in one portion. Afterstirring for 30 min at rt, 4-chloro-6,7-dimethoxyquinazoline (3.54 g,15.74 mmol) was added and the reaction mixture was heated at 50° C. for18 h. The reaction was cooled to rt, then diluted with dichloromethane.The solution was washed with water, then brine, and dried over MgSO₄.Filtration followed by concentration under reduced pressure gave a solidthat was triturated with a mixture of 10% dichloromethane in ethylacetate. Filtration afforded3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline (2.10 g, 42%) as acolorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (s, 1H), 7.54 (s, 1H),7.40 (s, 1H), 6.93 (dd, J=8.4, 8.4 Hz, 1H), 6.71 (dd, J=8.4, 8.4 Hz,1H), 6.53 (m, 1H), 5.37 (brs, 2H), 3.99 (s, 3H), 3.98 (s, 3H); LC-MS(ESI) m/z 316 (M+H)⁺.

Example 265B: To a stirred solution of3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline from the previousstep (150 mg, 0.476 mmol) and phenyl5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate describedin Example 260A (224 mg, 0.714 mmol) in anhydrous THF (5 mL), was added4-(dimethylamino)pyridine (6 mg, 0.0492 mmol) and the mixture wasstirred at rt for 15 h. An additional amount of5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (50 mg,0.159 mmol) was added, and stirred for an additional 15 h. Concentrationin vacuo followed by purification via silica gel column chromatography(eluted with a gradient of 20% ethyl acetate in hexanes to 100% ethylacetate), afforded1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea(137 mg, 54%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.01(brs, 1H), 8.89 (s, 1H), 8.58 (s, 1H), 8.07 (m, 1H), 7.59 (s, 1H), 7.43(s, 1H), 7.27 (m, 1H), 7.16 (m, 1H), 6.91 (s, 1H), 4.00 (s, 6H), 1.56(s, 6H); LC-MS (ESI) m/z 536 (M+H)⁺.

Example 266 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea

Example 266A Step 1: To a stirred solution of 4-fluoro-3-methoxyaniline(4.80 g, 34 mmol) in dichloromethane (50 mL), at −10° C., was added a4.0 M solution of boron tribromide in dichloromethane (20 mL, 80 mmol).The reaction mixture was allowed to warm to rt and stirring wascontinued for a further 15 h. The reaction mixture was quenched via theaddition of methanol. After concentration under reduced pressure, theresidue was taken up in water, basified with saturated sodium hydrogencarbonate solution, and extracted with ethyl acetate. The combined ethylacetate layers were washed with brine, dried over MgSO₄, andconcentrated under reduced pressure to afford 5-amino-2-fluorophenol(4.00 g, 93%) as a solid which was taken on without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 6.87 (dd, J=9.2, 9.2 Hz, 1H),6.35 (m, 1H), 6.16 (m, 1H), 5.09 (brs, 1H), 3.56 (brs, 2H); LC-MS (ESI)m/z 128 (M+H)⁺.

Example 266A Step 2: To a stirred slurry of cesium carbonate (9.53 g, 29mmol) in a mixture of THF/DMF (9/1, 200 mL) at rt, was added5-amino-2-fluorophenol (2.10 g, 14.6 mmol) in one portion. Afterstirring for 30 min at rt, 4-chloro-6,7-dimethoxyquinazoline (3.61 g, 16mmol) was added and the reaction mixture was heated at 50° C. for 30 h.The reaction was cooled to rt, then diluted with ethyl acetate. Thesolution was washed with 1 N sodium hydroxide solution, then brine, anddried over MgSO₄. Filtration followed by concentration under reducedpressure gave a solid that was triturated with methanol. Filtrationafforded 3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluoroaniline (3.10 g,67%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (s, 1H), 7.54(s, 1H), 7.41 (s, 1H), 7.05 (dd, J=9.2, 9.2 Hz, 1H), 6.47-6.56 (m, 2H),5.19 (brs, 2H), 4.00 (s, 3H), 3.99 (s, 3H); LC-MS (ESI) m/z 316 (M+H)⁺.

Example 266B: To a stirred solution of3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluoroaniline from the previousstep (150 mg, 0.476 mmol) and phenyl5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate describedin Example 260A (179 mg, 0.571 mmol) in anhydrous THF (5 mL), was added4-(dimethylamino)pyridine (6 mg, 0.0492 mmol) and the mixture wasstirred at rt for 15 h. Concentration in vacuo followed by purificationvia silica gel column chromatography (eluted with a gradient of 20%ethyl acetate in hexanes to 100% ethyl acetate), afforded1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea(35 mg, 14%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.79(brs, 1H), 9.01 (s, 1H), 8.58 (s, 1H), 7.70 (m, 1H), 7.58 (s, 1H),7.30-7.42 (m, 3H), 6.86 (s, 1H), 4.00 (s, 6H), 1.54 (s, 6H); LC-MS (ESI)m/z 536 (M+H)⁺.

Example 267 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)urea

Example 267A Step 1: 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile(524 mg, 2.9 mmol) described in Example 259A Steps 1 and 2 was taken inwater (2.9 ml), treated with sodium hydroxide (240 mg, 6 mmol) and theresulting solution stirred at rt for 15 min. After this timehydroxylamine hydrochloride (213 mg, 3.07 mmol) was added and themixture was heated at 80° C. for 2.5 h. After cooling to rt chloroformwas added (20 mL) and the organic phase separated. The water phase wasback extracted three times, the organics were combined, dried over MgSO₄and concentrated to afford3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (150 mg, 27%) asa solid, which was used without further purification. ¹H NMR (300 MHz,CDCl₃) δ 5.19 (s, 1H), 4.50 (brs, 2H), 1.54 (s, 6H); LC-MS (ESI) m/z 195(M+H)⁺.

Example 267A Step 2:3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (150 mg, 0.77mmol) dissolved in THF (2.5 mL) was treated with potassium carbonate(139 mg, 1.0 mmol) and p-chlorophenyl choloroformate (412 mg, 2.15mmol). The reaction mixture was stirred at rt overnight. The mixture wasfiltered through a celite pad, washed with ethyl acetate andconcentrated to dryness. The residue was taken into ethyl acetate,washed with brine, and the organics dried over MgSO₄ and concentrated.The residue was purified by silica gel chromatography (hexane/ethylacetate 8:2) to afford 4-chlorophenyl3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate (210 mg,78%) as a colorless solid. ¹H NMR (300 MHz, CDCl₃) δ 7.72 (brs, 1H),7.39 (d, J=12 Hz, 2H), 7.16 (d, J=12 Hz, 2H), 6.27 (s, 1H), 1.57 (s,6H); LC-MS (ESI) m/z 349 (M+H)⁺.

Example 267B: To a stirred solution of3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol) describedin Example 113A in anhydrous THF (1.5 mL), was added 4-chlorophenyl3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate from theprevious step (104 mg, 0.3 mmol) and 4-(dimethylamino)pyridine (18 mg,0.15 mmol). The mixture was stirred at rt for 6 h. Concentration invacuo followed by purification by silica gel chromatography(dichloromethane/ethyl acetate 1:1) afforded1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)urea(79.9 mg, 51%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.44(s, 1H), 9.11 (s, 1H), 8.56 (s, 1H), 7.56-7.58 (m, 2H), 7.40-7.45 (m,2H), 7.29-7.32 (m, 2H), 6.99-7.02 (m, 2H), 6.18 (s, 1H), 4.00 (s, 6H),1.24 (s, 6H); LC-MS (ESI) m/z 518 (M+H)⁺.

Example 268 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)urea

To a stirred solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (76mg, 0.24 mmol) described in Example 115B in anhydrous THF (1.5 mL), wasadded 4-chlorophenyl3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate fromExample 267A (84 mg, 0.24 mmol) and 4-(dimethylamino)pyridine (15 mg,0.12 mmol). The mixture was stirred at rt for 6 h. To the suspension wasadded diethyl ether. Sonication and filtration afforded1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)urea(88.8 mg, 69%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.48(s, 1H), 9.17 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.56 (d, J=9 Hz, 1H),7.43-7.48 (m, 1H), 7.30-7.36 (m, 3H), 6.19 (s, 1H), 3.99 (s, 6H), 1.49(s, 6H); LC-MS (ESI) m/z 534 (M+H)⁺.

Example 269 Preparation of1-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea

Example 269A: To a stirred suspension of cesium carbonate (3.25 g, 10.0mmoles) in dry DMF (20 mL) was added 5-amino-2,4-difluorophenol (1.00 g,6.9 mmoles). This solution was heated to 80° C. for 1 hour, and4-chloro-6,7-dimethoxyquinazoline (1.59 g, 7.1 mmoles) was added and thereaction heated for an additional hour. At the end of this time thereaction was poured into water (200 mL) and extracted with two portions(200 mL) of ethyl acetate. The extracts were combined and dried overMgSO₄. Filtration and concentration afforded5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluoroaniline as a crude redoil. Purification by silica gel chromatography eluting with an ethylacetate/hexane gradient, 30%-70% over 70 minutes gave a slightly impureoil containing DMF. This oil was crystallized using ethyl acetate hexaneto give a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 8.56 (s, 1H), 7.53 (s, 1H), 7.39 (s, 1H),7.27 (m, 1H), 6.76 (m, 3H), 5.22 (s, 2H), 3.98 (s, 6H); LCMS (ESI) m/z334 (M+H)⁺

Example 269B: To a stirred solution of5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluoroaniline (100 mg, 0.3mmoles) from the previous step and phenyl3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate described in Example 42A(96 mg, 0.32 mmoles) in anhydrous DMF (10 mL), was added4-(dimethylamino)pyridine (20 mg, 0.16 mmoles) and diisopropylethylamine(80 μL, 0.45 mmoles) and the reaction heated to 70 C overnight. Thereaction was then concentrated to an oil and purified by silica gelchromatography eluting with a gradient of ethyl acetate/dichloromethane,3-80%, to afford1-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea(46.33 mg, 31% yield) as a white solid. ¹H (300 MHz, DMSO-d₆) δ 10.58(s, 1H), 8.92 (s, 1H), 8.57 (s, 1H), 8.13 (m, 1H), 7.67 (m, 1H), 7.57(s, 1H), 7.41 (s, 1H), 6.12 (s, 1H), 3.98 (s, 6H), 1.65 (d, J=21 Hz,6H); LCMS (ESI) m/z (M+H)⁺ 504.

Example 270 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)urea

Example 270A: To a solution of 5-tert-butylisoxazol-3-amine (35.00 g,250 mmol) in THF (300 mL), potassium carbonate (45.61 g, 330 mmol) andphenyl chloroformate (43.84 g, 280 mmol) were added and the solutionstirred at rt overnight. The reaction mixture was filtered throughCelite and the pad washed thoroughly with THF. The filtrate wasconcentrated to a solid and portioned between brine and DCM, thenextracted with 2 additional portions of DCM. The combined extracts weredried over magnesium sulfate, filtered and concentrated to a solid. Theresulting solid was recrystallized from 10% DCM/ether and hexane. Thesolid collected by filtration to afford phenyl5-tert-butylisoxazol-3-ylcarbamate (50.72 g, 78% yield). ¹H NMR (300MHz, DMSO d6) δ 1.35 (s, 9H), 6.43 (s, 1H), 7.20 (m, 3H), 7.44 (m, 2H).

Example 270B: To a solution of5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluoroaniline (100 mg, 0.3mmol) in THF (10 mL), DIEA (58 mg, 0.45 mmol), DMAP (20 mg, 0.16 mmol),and phenyl 5-tert-butylisoxazol-3-ylcarbamate (117 mg, 0.32 mmol) wereadded and the mixture heated overnight at 70° C. The mixture was pouredinto water and extracted with EtOAc three times. The extracts were driedover magnesium sulfate, filtered, and concentrated. The residue waspurified using silica gel chromatography eluting with EtOAc/Hexane(3-80%). The appropriate fractions were concentrated to afford1-(5-tert-butylisoxazol-3-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)urea(37.56 mg, 25% yield). ¹H NMR (300 MHz, CDCl₃) δ 1.35 (s, 9H), 4.05 (s,6H), 6.09 (s, 1H), 6.85 (s, 1H), 7.28 (s, 1H), 7.35 (s, 1H), 8.28 (m,1H), 8.70 (s, 1H), 9.50 (s, 1H). LC-MS (ESI) m/z 500 (M+H)⁺

Example 271 Preparation of1-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

1-(5-(6,7-Dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)ureawas obtained following the procedure described in Example 274B forsynthesis of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea,substituting phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate withphenyl 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate in Example161, and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline with5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluoroaniline in Example 269(0.153 g, 65%). ¹H NMR (300 MHz, DMSO-d₆) δ 3.99 (s, 3H), 4.00 (s, 3H),6.85 (s, 1H), 7.43 (s, 1H), 7.58-7.67 (m, 7H), 8.18 (t, 1H), 8.57 (s,1H), 9.21 (s, 1H), 9.26 (s, 1H); LC-MS (ESI) m/z 587 (M+H)⁺.

Example 272 Preparation of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)urea

The title compound was prepared from5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluoroaniline (100 mg, 0.3mmol) and phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (140mg, 0.4 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)urea(170 mg, 0.29 mmol, 96%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.86(s, 1H), 8.58 (s, 1H), 8.22 (t, 1H), 7.61 (t, 1H), 7.58 (s, 1H),7.42-7.34 (m, 5H), 6.35 (s, 1H), 4.01 (s, 3H), 4.00 (s, 3H), 2.39 (s,3H), 1.28 (s, 9H); LC-MS (ESI) m/z 589 (M+H)⁺.

Example 273 Preparation of1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)urea

The title compound was prepared from3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate described in Example 153A(100 mg, 0.30 mmol) and5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluoroaniline (100 mg, 0.30mmol) using the procedure in Example 115C to give1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea(90 mg, 0.16 mmol, 52%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.92(s, 1H), 8.59 (s, 1H), 8.23 (2, 1H), 7.54-7.43 (m, 8H), 6.38 (s, 1H),4.00 (s, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 575 (M+H)⁺.

Example 274 Preparation of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 274A Step 1: A mixture of 4,4-dimethyl-3-oxopentanenitrile(2.503 g, 20 mmol) and p-tolylhydrazine hydrochloride (3.173 g, 20 mmol)in EtOH was heated at 90° C. for 8 hours. The reaction was quenched byadding water and extracted with DCM. Extracts were dried over MgSO₄ andconcentrated to give 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine as solid(4.537 g, 99%). ¹H NMR (300 MHz, CDCl₃) δ 1.31 (s, 9H), 2.36 (s, 3H),3.69 (s, 2H), 5.51 (s, 1H), 7.25 (d, 2H), 7.44 (d, 2H); LC-MS (ESI) m/z230 (M+H)⁺.

Example 274A Step 2: To a suspension of3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (4.53 g, 19.8 mmol) and K₂CO₃(4.146 g, 30 mmol) in THF (30 mL) was added phenyl chloroformate (4.071g, 26 mmol). It was stirred at room temperature overnight. The reactionwas quenched by adding water and extracted with DCM. Extracts were driedover MgSO₄ and concentrated. The crude product was purified on a silicagel column using a mixture of EtOAc-hexane as eluent to give phenyl3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate as solid (5.12 g, 74%).¹H NMR (300 MHz, CDCl₃) δ 1.34 (s, 9H), 2.43 (s, 3H), 6.5 (s, 1H), 7.0(s, 1H), 7.15 (d, 2H), 7.36 (m, 7H); LC-MS (ESI) m/z 350 (M+H)⁺.

Example 274B: A mixture of phenyl3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (0.14 g, 0.4 mmol),3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113 (0.119 g,0.4 mmol) and DMAP (0.025 g) in THF (6 mL) was stirred at roomtemperature overnight. The reaction was quenched by adding DCM andconcentrated. To the residue was added Et2O to give1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)ureaas solid (0.181 g, 82%). ¹H NMR (300 MHz, DMSO-d₆) δ 1.25 (s, 9H), 2.37(s, 3H), 3.98 (s, 3H), 3.99 (s, 3H), 6.33 (s, 1H), 6.93 (d, 1H), 7.16(d, 1H), 7.32-7.40 (m, 6H), 7.55 (d, 2H), 8.41 (s, 1H), 8.55 (s, 1H),9.23 (s, 1H); LC-MS (ESI) m/z 553 (M+H)⁺.

Example 275 Preparation of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

1-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)ureawas obtained following the procedure described in Example 274B forsynthesis of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea,substituting 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline with3-(6,7-dimethoxyquinazolin-4-ylthio)aniline in Example 115 (0.174 g, 77%yield). ¹H NMR (300 MHz, DMSO-d₆) δ 1.26 (s, 9H), 2.37 (s, 3H), 3.99 (s,6H), 6.34 (s, 1H), 7.24 (dd, 1H), 7.32-7.44 (m, 8H), 7.79 (s, 1H), 8.40(s, 1H), 8.69 (s, 1H), 9.23 (s, 1H); LC-MS (ESI) m/z 569 (M+H)⁺.

Example 276 Preparation of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)ureawas obtained following the procedure described in Example 274B forsynthesis of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea,substituting 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline with3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline in Example117 (0.196 g, 82% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 1.25 (s, 9H), 2.37(s, 3H), 3.35 (s, 3H), 3.76 (t, 2H), 3.98 (s, 3H), 4.34 (t, 2H), 6.33(s, 1H), 6.93 (d, 1H), 7.16 (d, 1H), 7.31-7.41 (m, 6H), 7.56 (s, 2H),8.41 (s, 1H), 8.55 (s, 1H), 9.22 (s, 1H); LC-MS (ESI) m/z 597 (M+H)⁺.

Example 277 Preparation of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea

1-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)ureawas obtained following the procedure described in Example 274B forsynthesis of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea,substituting 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline with3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline in Example231 (0.153 g, 62% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 1.26 (s, 9H), 2.37(s, 3H), 3.34 (s, 3H), 3.76 (t, 2H), 3.99 (s, 3H), 4.33 (t, 2H), 6.34(s, 1H), 7.23 (dd, 1H), 7.25-7.44 (m, 8H), 7.79 (s, 1H), 8.41 (s, 1H),8.68 (s, 1H), 9.24 (s, 1H); LC-MS (ESI) m/z 613 (M+H)⁺.

Example 278 Preparation of1-(3-(2-cyanopropan-2-yl)phenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 278A Step 1: To an ice-cold suspension of 95% NaH (1.03 g, 43mmol) in anhydrous THF (15 ml) was added dropwise a solution of2-(3-nitrophenyl)acetonitrile (2.2 g, 13.58 mmol) in 5 ml THF. Themixture was stirred at 0° C. for 30 min. After this time methyl iodide(6.8 ml, 107 mmol) was added dropwise at 0° C. After the addition wascomplete the reaction mixture was allowed to warm to rt and stirredovernight. The solvent was removed under reduced pressure and theresidue taken in EtOAc, washed with water and brine and the organicscombined, dried (MgSO₄) and concentrated. The residue was purified bysilica gel chromatography (hexane/ethyl acetate 5%) to afford2-methyl-2-(3-nitrophenyl)propanenitrile (800 mg, 31%) as a solid. ¹HNMR (300 MHz, DMSO-d6) δ 1.85 (s, 6H), 4.50 (brs, 2H), 7.74-7.79 (m,1H), 8.04 (d, J=12 Hz, 1H), 8.27 (d, J=12 Hz, 1H), 8.33 (s, 1H); LC-MS(ESI) m/z 191 (M+H)⁺.

Example 278A Step 2: To a suspension of tin (II) chloride bis hydrate(3.3 g, 13.1 mmol) in EtOH (25 mL) was added2-methyl-2-(3-nitrophenyl)propanenitrile (800 mg, 4.2 mmol). Thereaction mixture was stirred at 90° C. for 1 h. After cooling down tort, the solvent was removed under reduced pressure and the residue takenin DCM, washed with water and a saturated solution of sodium hydrogencarbonate until pH=8. After combining, the organics were dried (MgSO₄)and concentrated. The residue was purified by silica gel chromatography(hexane/ethyl acetate 15%) to afford2-(3-aminophenyl)-2-methylpropanenitrile (490 mg, 73%) as a colorlesssolid. ¹H NMR (300 MHz, CDCl₃) δ 1.69 (s, 6H), 3.75 (brs, 2H), 6.64 (d,J=9 Hz, 1H), 6.80-6.83 (m, 2H), 7.15-7.19 (m, 1H); LC-MS (ESI) m/z 161(M+H)⁺.

Example 278A Step 3: To a solution of2-(3-aminophenyl)-2-methylpropanenitrile (490 mg, 3.06 mmol) andpotassium carbonate (552 mg, 4 mmol) in anhydrous THF (4.2 ml) was addeddropwise phenyl chloroformate (0.81 ml, 6.4 mmol) as a solution in THF(2 ml). The reaction mixture was stirred at rt overnight. The solventwas removed and the residue taken in DCM, washed with water and brineand the organics combined, dried (MgSO₄) and concentrated. The crude waspurified by silica gel chromatography (hexane/ethyl acetate 15%) toafford phenyl 3-(2-cyanopropan-2-yl)phenylcarbamate (828 mg, 96%) as asolid. ¹H NMR (300 MHz, CDCl₃) δ 1.72 (s, 6H), 7.20-7.28 (m, 4H),7.35-7.41 (m, 4H), 7.65 (s, 1H); LC-MS (ESI) m/z 281 (M+H)⁺.

Example 278B: To a solution of3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (47 mg, 0.15 mmol), preparedas described in Example 113A, in THF (3 ml) was added DMAP (18 mg, 0.15mmol) and phenyl 3-(2-cyanopropan-2-yl)phenylcarbamate (89 mg, 0.3mmol). The reaction mixture was stirred at rt for 24 h. Concentrationunder reduced pressure gave a residue which was purified by preparativeHPLC (Phenomenex phenylhexyl reverse phase column). The obtained solidwas triturated with anhydrous diethyl ether to afford1-(3-(2-cyanopropan-2-yl)phenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(14.9 mg, 20%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.66 (s, 6H),3.99 (s, 6H), 6.92 (d, J=8.7 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 7.30-7.40(m, 4H), 7.57-7.66 (m, 4H), 8.56 (s, 1H), 8.90 (d, J=7.5 Hz, 2H); LC-MS(ESI) m/z 484 (M+H)¹

Example 279 Preparation of1-(3-(2-cyanopropan-2-yl)phenyl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

To a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3mmol), prepared as described in Example 115B, in THF (3 ml) was addedDMAP (18 mg, 0.15 mmol) and phenyl 3-(2-cyanopropan-2-yl)phenylcarbamate(92 mg, 0.33 mmol) described in Example 278A. The reaction mixture wasstirred at rt for 24 h. Concentration under reduced pressure gave aresidue which was triturated with anhydrous diethyl ether to afford1-(3-(2-cyanopropan-2-yl)phenyl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(64.1 mg, 43%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.67 (s, 6H),3.99 (s, 6H), 7.11 (d, J=6.6 Hz, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.30-7.45(m, 5H), 7.53 (d, J=8.1 Hz, 1H), 7.66 (s, 1H), 7.84 (s, 1H), 8.70 (s,1H), 8.91 (d, J=6.6 Hz, 2H); LC-MS (ESI) m/z 500 (M+H)⁺.

Example 280 Preparation of1-(3-(2-cyanopropan-2-yl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea

Using the procedure described in Example 279a solution of3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline (103 mg, 0.3mmol), prepared as described in Example 117B, in THF (3 ml) was addedDMAP (18 mg, 0.15 mmol) and phenyl 3-(2-cyanopropan-2-yl)phenylcarbamate(92 mg, 0.33 mmol) described in Example 278A to afford1-(3-(2-cyanopropan-2-yl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea(86.6 mg, 55%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.66 (s, 6H),3.78 (s, 3H), 3.98 (s, 4H), 4.34 (s, 3H), 6.95 (d, J=7.8 Hz, 1H), 7.11(d, J=7.8 Hz, 1H), 7.26-7.41 (m, 5H), 7.58-7.66 (s, 3H), 8.54 (s, 1H),8.90 (d, J=8.4 Hz, 2H); LC-MS (ESI) m/z 528 (M+H)⁺.

Example 281 Preparation of1-(3-(2-cyanopropan-2-yl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea

Using the procedure described in Example 278B, to a solution of3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline (102 mg, 0.3mmol), prepared as described in Example 230A, in THF (3 ml) was addedDMAP (18 mg, 0.15 mmol) and phenyl 3-(2-cyanopropan-2-yl)phenylcarbamate(92 mg, 0.33 mmol) described in Example 278A to afford1-(3-(2-cyanopropan-2-yl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea(37.2 mg, 23%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.67 (s, 6H),3.76 (s, 3H), 4.00 (s, 4H), 4.34 (s, 3H), 7.11 (d, J=6 Hz, 1H),7.24-7.43 (m, 7H), 7.66 (s, 1H), 7.84 (s, 1H), 8.69 (s, 1H), 8.92 (d,J=9 Hz, 2H); LC-MS (ESI) m/z 544 (M+H)⁺.

Example 282 Preparation of1-(3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 282A Step 1:To a heated solution of 2,4-dimethylphenylhydrazinehydrochloride (1.38 g, 8 mmol) in EtOH/water/1M NaOH (20 mL/12 mL/8 mL)at 50° C., 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8 mmol) was addedand the reaction heated until finished by LC-MS. The solution waspartitioned between EtOAc and water, and extracted twice. The extractswere washed with brine, dried with magnesium sulfate, filtered, andconcentrated. Purification using silica gel chromatography eluting withan EtOAC/hexane gradient (5-20%) gave3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-amine (700 mg, 36%yield). ¹H NMR (300 MHz, DMSO d₆) δ 1.09 (s, 9H), 1.98 (s, 3H), 2.32 (s,3H), 4.76 (s, 2H), 5.26 (s, 1H), 7.11 (m, 3H). LC-MS (ESI) m/z 244(M+H)⁺.

Example 282A Step 2: To a solution of3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-amine (700 mg, 2.9mmol) in DCM (20 mL) was added K₂CO₃ (4.32 mmol) and phenylchloroformate (6.48 mmol) and the reaction stirred overnight. Thesolvent was decanted and the solids washed with DCM. The combinedorganics were concentrated and purified using silica gel chromatographyeluting with an EtOAC/hexane gradient (5-20%) gave phenyl3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-ylcarbamate (472 mg,45% yield). ¹H NMR (300 MHz, DMSO d₆) δ 1.09 (s, 9H), 1.98 (s, 3H), 2.36(s, 3H), 6.26 (s, 1H), 7.00 (s, 2H), 7.14 (m, 4H), 7.37 (m, 2H), 9.80(bs, 1H); LC-MS (ESI) m/z 364 (M+H)⁺

Example 282B: The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol) and phenyl3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-ylcarbamate from Step A(120 mg, 0.33 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(141 mg, 0.25 mmol, 83%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.55(s, 1H), 8.19 (s, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 7.39 (s, 1H), 7.36(t, 1H), 7.23-7.11 (m, 4H), 6.94 (d, 1H), 6.33 (s, 1H), 4.00 (s, 3H),3.98 (s, 3H), 2.37 (s, 3H), 1.95 (s, 3H), 1.26 (s, 9H); LC-MS (ESI) m/z567 (M+H)⁺.

Example 283 Preparation of1-(3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea

The title compound was prepared from3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described inExample 230A (94 mg, 0.27 mmol) and phenyl3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-ylcarbamate (120 mg,0.33 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea(130 mg, 0.21 mmol, 77%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.68(s, 1H), 8.18 (s, 1H), 7.79 (s, 1H), 7.43-7.38 (m, 2H), 7.36 (s, 1H),7.32 (s, 1H), 7.25-7.16 (m, 4H), 6.34 (s, 1H), 4.33 (t, 2H), 3.99 (s,3H), 3.76 (t, 2H), 3.34 (s, 3H), 2.37 (s, 3H), 1.95 (s, 3H), 1.27 (s,9H); LC-MS (ESI) m/z 627 (M+H)⁺.

Example 284 Preparation of1-(3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol) and thecarbamate described in Example 282A (120 mg, 0.33 mmol) using theprocedure in Example 115C to give1-(3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(152 mg, 0.26 mmol, 87%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.68(s, 1H), 8.18 (s, 1H), 7.79 (s, 1H), 7.43-7.38 (m, 2H), 7.34 (s, 1H),7.32 (s, 1H), 7.26-7.16 (m, 4H), 6.33 (s, 1H), 3.99 (s, 6H), 2.37 (s,3H), 1.95 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 583 (M+H)⁺.

Example 285 Preparation of1-(3-tert-butyl-1-m-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol) and phenyl3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-ylcarbamate (115 mg,0.33 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-m-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(164 mg, 0.30 mmol, 99%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.24 (s, 1H), 8.56(s, 1H), 8.45 (s, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 7.44-7.28 (m, 5H),7.23 (d, 1H), 7.18 (d, 1H), 6.93 (d, 1H), 6.35 (s, 1H), 3.99 (s, 3H),3.98 (s, 3H), 2.38 (s, 3H), 1.26 (s, 9H); LC-MS (ESI) m/z 553 (M+H)⁺.

Example 286 Preparation of1-(3-tert-butyl-1-m-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

Example 286A Step 1:The procedure described in Example 282A Step 1 wasfollowed to obtain1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine, bysubstituting m-tolylhydrazine for 2,4-dimethylphenylhydrazinehydrochloride to afford 3-tert-butyl-1-m-tolyl-1H-pyrazol-5-amine (903mg, 58% yield). LC-MS (ESI) m/z 230 (M+H)⁺.

Example 286A Step 2: Phenyl3-tert-butyl-1-m-tolyl-1H-pyrazol-5-ylcarbamate was obtained using theprocedure described in Example 282A Step 2, using3-tert-butyl-1-m-tolyl-1H-pyrazol-5-amine from the previous step (650mg, 47% yield). ¹H NMR (300 MHz, DMSO d₆) δ 1.30 (s, 9H), 2.39 (s, 3H),6.35 (s, 1H), 7.10 (bs, 2H), 7.23 (m, 2H), 7.42 (m, 5H), 10.0 (bs, 1H);LC-MS (ESI) m/z 350 (M+H)⁺.

Example 286B: The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol) and phenyl3-tert-butyl-1-m-tolyl-1H-pyrazol-5-ylcarbamate from the previous step(115 mg, 0.33 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-m-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(145 mg, 0.26 mmol, 85%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (s, 1H), 8.69(s, 1H), 8.45 (s, 1H), 7.80 (s, 1H), 7.48-7.16 (m, 9H), 6.36 (s, 1H),3.99 (s, 6H), 2.38 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 569 (M+H)⁺.

Example 287 Preparation of1-(3-tert-butyl-1-m-tolyl-1H-pyrazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea

The title compound was prepared from3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline (94 mg, 0.27mmol) and phenyl 3-tert-butyl-1-m-tolyl-1H-pyrazol-5-ylcarbamate (115mg, 0.33 mmol) using the procedure in Example 115C to give the titlecompound (145 mg, 0.24 mmol, 88%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (s,1H), 8.67 (s, 1H), 8.45 (s, 1H), 7.81 (s, 1H), 7.48-7.21 (m, 9H), 6.37(s, 1H), 4.32 (t, 2H), 3.99 (s, 3H), 3.76 (t, 2H), 3.36 (s, 3H), 2.38(s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 613 (M+H)⁺.

Example 288 Preparation of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylphenyl)urea

Following the procedure for Example 298A, substituting3-amino-4-chlorophenol with 3-amino-2-methylphenol, and precipitatingthe compound out of water, after collecting by filtration and drying,3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylaniline was isolated in 88%yield. ¹H NMR (300 MHz, DMSO d₆) δ 1.79 (s, 3H), 3.96 (s, 6H), 6.36 (d,1H), 6.56 (d, 1H), 6.95 (t, 1H), 7.37 (s, 1H), 7.56 (s, 1H), 8.49 (s,1H); LC-MS (ESI) m/z 312 (M+H)⁺

The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylaniline (93 mg, 0.3 mmol)and phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (105 mg, 0.3mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylphenyl)urea(134 mg, 0.24 mmol, 79%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.52(s, 1H), 8.41 (s, 1H), 7.72 (d, 1H), 7.60 (s, 1H), 7.47-7.32 (m, 5H),7.25 (t, 1H), 6.96 (d, 1H), 6.37 (s, 1H), 3.99 (s, 6H), 2.36 (s, 3H),1.95 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 567 (M+H)⁺.

Example 289 Preparation of1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylphenyl)urea

The title compound was prepared from phenyl3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (100 mg, 0.30 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylaniline (94 mg, 0.30 mmol)using Example 115C to give1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylphenyl)urea(106 mg, 0.19 mmol, 64%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.55(s, 1H), 8.41 (s, 1H), 7.72 (d, 1H), 7.59-7.51 (m, 5H), 7.39 (br s, 2H),7.24 (t, 1H), 6.96 (d, 1H), 6.39 (s, 1H), 4.02 (s, 6H), 1.96 (s, 3H),1.28 (s, 9H); LC-MS (ESI) m/z 553 (M+H)⁺.

Example 290 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylphenyl)urea

Following the procedure for Example 270B, substituting the aniline with3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylaniline, and after silicagel chromatography,1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylphenyl)ureawas isolated in 22% yield. ¹H NMR (300 MHz, CDCl₃) δ 1.35 (s, 9H), 2.22(S, 3H), 4.05 (s, 6H), 6.08 (s, 1H), 7.05 (m, 1H), 7.25 (m, 2H), 7.62(s, 1H), 7.95 (m, 1H), 8.75 (s, 1H), 9.15 (s, 1H). LC-MS (ESI) m/z 478(M+H)⁺

Example 291 Preparation of1-(3-(6,7-Dimethoxyquinazolin-4-yloxy)-2-methylphenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

1-(3-(6,7-Dimethoxyquinazolin-4-yloxy)-2-methylphenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)ureawas obtained following the procedure described in Example 274B forsynthesis of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea,substituting phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate withphenyl 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate in Example161, and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline with3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylaniline (0.040 g, 18%). ¹HNMR (300 MHz, DMSO-d₆) δ 1.93 (s, 3H), 3.98 (s, 3H), 3.99 (s, 3H), 6.89(s, 1H), 6.99 (d, 1H), 7.26 (t, 1H), 7.40 (s, 1H), 7.56-7.68 (m, 7H),8.51 (s, 1H), 8.54 (s, 1H), 9.11 (s, 1H); LC-MS (ESI) m/z 565 (M+H)⁺.

Example 292 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylphenyl)-3-(5-(2-fluoropropan-2-yl)isoxazol-3-yl)urea

The title compound was made following the procedure for Example 290B butsubstituting the carbamate with phenyl5-(2-fluoropropan-2-yl)isoxazol-3-ylcarbamate. After purification usingsilica gel chromatography,1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylphenyl)-3-(5-(2-fluoropropan-2-yl)isoxazol-3-yl)ureawas isolated in 21% yield. ¹H NMR (300 MHz, DMSO d₆) δ 1.71 (d, 6H),2.00 (s, 3H), 4.00 (s, 6H), 6.16 (s, 1H), 7.04 (m, 1H), 7.29 (m, 1H),7.40 (s, 1H), 7.60 (s, 1H), 7.75 (m, 1H), 8.34 (s, 1H), 8.52 (s, 1H),10.61 (s, 1H). LC-MS (ESI) m/z 482(M+H)⁺.

Example 293 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea

A mixture of 4-chlorophenyl3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate (prepared as described inExample 257A) (170 mg, 0.571 mmol),3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluoroaniline (prepared asdescribed in Example 266A steps 1 and 2) (150 mg, 0.475 mmol) andN,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) wasstirred at rt for 15 h. The reaction mixture was concentrated underreduced pressure to give the crude product. Purification via silica gelflash chromatography (eluting with a gradient of 20% ethyl acetate inhexanes to 100% ethyl acetate) afforded1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea(147 mg, 64%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.44(brs, 1H), 9.08 (brs, 1H), 8.58 (s, 1H), 7.69 (m, 1H), 7.59 (s, 1H),7.35-7.42 (m, 3H), 6.14 (s, 1H), 4.00 (s, 6H), 1.67 (d, J=21 Hz, 6H);LC-MS (ESI) m/z 486 (M+H)⁺.

Example 294 Preparation of1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)urea

A mixture of phenyl5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (prepared asdescribed in Example 162A steps 1 and 2) (169 mg, 0.571 mmol),3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline (prepared asdescribed in Example 265A steps 1 through 3) (150 mg, 0.475 mmol) andN,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) wasstirred at rt for 15 h. Additional phenyl5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (75 mg, 0.238mmol) was added and the mixture stirred for a further 19 h. The reactionmixture was concentrated under reduced pressure to give the crudeproduct. Purification via silica gel flash chromatography (eluting witha gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate)afforded1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)urea(147 mg, 60%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.73(brs, 1H), 8.99 (brs, 1H), 7.71 (s, 1H), 7.70 (m, 1H), 7.58 (s, 1H),7.31-7.42 (m, 3H), 6.76 (s, 1H), 4.63 (d, J=48 Hz, 4H), 4.01 (s, 6H),1.32 (s, 3H); LC-MS (ESI) m/z 518 (M+H)⁺.

Example 295 Preparation of1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea

A mixture of phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate(prepared as described in Example 153A) (239 mg, 0.71 mmol),3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline (prepared asdescribed in Example 265A steps 1 through 3) (150 mg, 0.475 mmol) andN,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) wasstirred at rt for 15 h. The reaction mixture was concentrated underreduced pressure to give the crude product. Purification via silica gelflash chromatography (eluting with a gradient of 20% ethyl acetate inhexanes to 100% ethyl acetate) afforded1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea(167 mg, 63%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.07(brs, 1H), 8.85 (brs, 1H), 8.57 (s, 1H), 8.07 (m, 1H), 7.39-7.58 (m,7H), 7.23 (m, 1H), 7.20 (m, 1H), 6.42 (s, 1H), 4.00 (s, 3H), 3.99 (s,3H), 1.29 (s, 9H); LC-MS (ESI) m/z 557 (M+H)⁺.

Example 296 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea

A mixture of 4-chlorophenyl3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate (prepared as described inExample 257A) (213 mg, 0.714 mmol),3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline (prepared asdescribed in Example 265A steps 1 through 3) (150 mg, 0.475 mmol) andN,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) wasstirred at rt for 15 h. The reaction mixture was concentrated underreduced pressure to give the crude product. Purification via silica gelflash chromatography (eluting with a gradient of 20% ethyl acetate inhexanes to 100% ethyl acetate) afforded1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea(147 mg, 64%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.55(brs, 1H), 8.89 (brs, 1H), 8.58 (s, 1H), 8.03 (m, 1H), 7.59 (s, 1H),7.43 (s, 1H), 7.28 (m, 1H), 7.18 (m, 1H), 6.20 (s, 1H), 4.00 (s, 6H),1.69 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 486 (M+H)⁺.

Example 297 Preparation of1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea

A mixture of phenyl5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (prepared asdescribed in Example 162A steps 1 and 2) (211 mg, 0.714 mmol),3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline (prepared asdescribed in Example 265A steps 1 through 3) (150 mg, 0.475 mmol) andN,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) wasstirred at rt for 36 h. The reaction mixture was concentrated underreduced pressure to give the crude product. Purification via silica gelflash chromatography (eluting with a gradient of 20% ethyl acetate inhexanes to 100% ethyl acetate) afforded1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea(104 mg, 42%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) 89.96(brs, 1H), 8.87 (brs, 1H), 8.58 (s, 1H), 8.08 (m, 1H), 7.59 (s, 1H),7.43 (s, 1H), 7.27 (m, 1H), 7.15 (m, 1H), 6.81 (s, 1H), 4.66 (d, J=47Hz, 4H), 4.01 (s, 6H), 1.34 (s, 3H); LC-MS (ESI) m/z 518 (M+H)⁺.

Example 298 Preparation of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 298A: A solution of 3-amino-4-chlorophenol (1.00 g, 7.0 mmol)and cesium carbonate (3.38 g, 10.4 mmol) in DMF (20 mL) were heated at80 C for 1 hr. The chloroquinazoline (1.61 g, 7.2 mmol) was added andthe mixture heated for an additional hour. The mixture was poured intowater (300 mL) and extracted with EtOAc twice. The combined extractswere washed with brine, dried with magnesium sulfate, filtered andconcentrated. The residue was purified using silica gel chromatographyeluting with EtOAc/hexane (30-70%), the main peak collected andtriturated with DCM to afford2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)aniline. ¹H NMR (300 MHz,DMSO d₆) δ 3.96 (s, 6H), 5.55 (s, 2H), 6.45 (t, 1H), 6.76 (d, 1H), 7.25(d, 1H), 7.36 (s, 1H), 7.50 (s, 1H), 8.55 (s, 1H); LC-MS (ESI) m/z 332(M+H)⁺

Example 298B: The title compound was prepared from2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)aniline (100 mg, 0.3 mmol)and phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (140 mg, 0.4mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(80 mg, 0.14 mmol, 46%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H), 8.82(s, 1H), 8.56 (s, 1H), 8.12 (d, 1H), 7.57-7.54 (m, 2H), 7.40-7.33 (m,5H), 7.03 (dd, 1H), 6.34 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 2.37 (s,3H), 1.27 (s, 9H); LC-MS (ESI) m/z 587 (M+H)⁺.

Example 299 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Following the procedure for Example 270B, but substituting the anilinewith 2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)aniline,1-(5-tert-butylisoxazol-3-yl)-3-(2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(19% yield) was obtained. ¹H NMR (300 MHz, CDCl₃) δ 1.35 (s, 9H), 4.05(s, 6H), 6.08 (s, 1H), 7.00 (m, 1H), 7.35 (m, 2H), 7.55 (s, 1H), 8.35(s, 1H), 8.82 (s, 1H), 9.22 (s, 1H). LC-MS (ESI) m/z 498 (M+H)⁺

Example 300 Preparation of1-(2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

The title compound was obtained following the procedure described inExample 274B for synthesis of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea,but substituting phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamatewith phenyl 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate inExample 161, and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline with2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)aniline (0.075 g, 32%). ¹HNMR (300 MHz, DMSO-d₆) δ 3.99 (s, 3H), 4.00 (s, 3H), 6.86 (s, 1H), 7.08(d, 1H), 7.41 (s, 1H), 7.56-7.63 (m, 7H), 8.09 (d, 1H), 8.56 (s, 1H),8.95 (s, 1H), 9.63 (s, 1H); LC-MS (ESI) m/z 585 (M+H)⁺.

Example 301 Preparation of1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

The title compound was prepared from3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (100 mg, 0.30 mmol) and2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)aniline (100 mg, 0.30 mmol)using the procedure in Example 115C to give1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(34 mg, 0.06 mmol, 20%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.33 (s, 1H), 8.81(s, 1H), 8.56 (s, 1H), 8.11 (s, 1H), 7.57-7.52 (m, 6H), 7.44-7.40 (m,2H), 7.01 (d, 1H), 6.36 (s, 1H), 3.98 (s, 6H), 1.24 (s, 9H); LC-MS (ESI)m/z 573 (M)⁺.

Example 302 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-yl)urea

Example 302A Step 1: To a stirred solution of phenyl5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (prepared asdescribed in Example 131A steps 1 through 4) (250 mg, 0.91 mmol) andpyridine (0.15 mL, 1.81 mmol) in dichloromethane (5 mL) at 0° C., wasadded dropwise, 4-nitrophenylsulfonyl chloride (245 mg, 1.08 mmol) indichloromethane (3 mL). The reaction mixture was warmed to 35° C. andstirred for a further 15 h. Concentration under reduced pressure gavethe crude product which was purified via silica gel columnchromatography (eluting with 20% ethyl acetate in petroleum ether) toafford 2-methyl-2-(3-(phenoxycarbonylamino)isoxazol-5-yl)propyl4-nitrobenzenesulfonate (250 mg, 60%) as a yellow solid. ¹H NMR (400MHz, CDCl₃) δ 8.36-8.39 (m, 2H), 8.01-8.03 (m, 2H), 7.88 (m, 1H),7.43-7.45 (m, 2H), 7.21-7.31 (m, 3H), 6.54 (s, 1H), 4.19 (s, 2H), 1.38(s, 6H).

Example 302A Step 2: A stirred mixture of2-methyl-2-(3-(phenoxycarbonylamino)isoxazol-5-yl)propyl4-nitrobenzenesulfonate (130 mg, 0.22 mmol), magnesium oxide (45 mg,0.87 mmol), 1,4-dioxane (8 mL) and water (2 mL) was stirred at 60° C.for 5 h. The reaction mixture was cooled to rt and filtrated. Thefiltrate was concentrated under reduced pressure to give the crudeproduct. Purification via recrystallization from a 1:1 mixture ofdiethyl ether and hexane, afforded2-(3-aminoisoxazol-5-yl)-2-methylpropyl 4-nitrobenzenesulfonate (66 mg,69%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.38-8.40 (m,2H), 7.99-8.00 (m, 2H), 5.55 (s, 1H), 4.13 (s, 2H), 1.32 (s, 6H).

Example 302A Step 3: Six equivalent batches of a stirred mixture of2-(3-aminoisoxazol-5-yl)-2-methylpropyl 4-nitrobenzenesulfonate (50 mg,0.15 mmol), morpholine (0.016 mL, 0.179 mmol), DBU (0.027 mL, 0.179mmol) and acetonitrile (0.75 mL) were heated in a microwave reactor at140° C. for 2.5 h. After cooling to rt, the reactions were combined andconcentrated under reduced pressure. The residue was partitioned betweenchloroform and saturated aqueous sodium carbonate solution. The organiclayer was separated and washed with brine. The organic layer wasseparated and dried over sodium sulfate, filtrated and concentratedunder reduced pressure to give the crude product. Purification viasilica gel column chromatography (eluting with a gradient of 100%chloroform to 5% methanol in chloroform) afforded5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-amine (20 mg, 10%) as asolid.

Example 302A Step 4: To a stirred mixture of5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-amine (20 mg, 0.010 mmol)and potassium carbonate (25 mg, 0.181 mmol) in THF (6 mL) at 0° C., wasadded dropwise phenyl chloroformate (0.010 mL, 0.08 mmol). The reactionmixture was warmed to rt and stirred for a further 15 h. The reactionmixture was filtrated and the filtrate washed with saturated aqueoussodium carbonate, then brine, and concentrated under reduced pressure.The residue was dissolved in dichoromethane and dried over sodiumsulfate then filtrated. The filtrate was concentrated under reducedpressure to give the crude product. Purification via recrystallizationfrom a mixture of diethyl ether and hexanes, afforded phenyl5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-ylcarbamate (22 mg) whichwas used in the next step without further purification.

Example 302B: A stirred solution of phenyl5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-ylcarbamate (22 mg),N,N-diisopropylethylamine (12 mg, 0.093 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described inExample 113A) (15 mg, 0.051 mmol) in THF (0.5 mL) was heated at 60° C.for 15 h. The reaction mixture was cooled to rt and partitioned betweensaturated aqueous sodium carbonate and dichloromethane. The organiclayer was separated and concentrated under reduced pressure to give thecrude product. Purification via preparative TLC afforded1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-yl)urea(5 mg, 1% over three steps) as a solid. ¹H NMR (400 MHz, CDCl₃) δ 9.35(brs, 1H), 8.65 (brs, 2H), 7.66 (s, 1H), 7.57 (s, 1H), 7.29-7.41 (m,3H), 7.01 (m, 1H), 6.10 (s, 1H), 4.09 (s, 6H), 3.63-3.66 (m, 4H),2.40-2.70 (m, 6H), 1.32 (s, 6H); LC-MS (ESI) m/z 549 (M+H)⁺.

Example 303 Preparation of1-(3-tert-butyl-1-(4-methylpyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 303A Step 1: 3-Bromo-4-methyl-pyridine (1.0 g, 5.81 mmol) in 5mL dry toluene was treated with benzophenone hydrazone (1.25 g, 6.39mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (335 mg, 0.58mmol), and sodium tert-butoxide (840 mg, 8.72 mmol). The mixture wasdegassed with argon for 15 minutes. Added Pd(II)(OAc)₂ (130 mg, 0.58mmol) and stirred at 90° C. for 14 hours. Extracted using EtOAc/H₂O(3×200 mL EtOAc, 1×100 mL H₂O, 1×100 mL brine). Dried using Na₂SO₄ andthen purified by flash chromatography (silica, 10-50% EtOAc/Hexane) toafford 3-(2-(diphenylmethylene)hydrazinyl)-4-methylpyridine (1.00 g,3.48 mmol, 60%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.79 (s, 1H), 7.97 (d, 1H),7.67-7.52 (m, 6H), 7.45-7.36 (m, 5H), 7.06 (d, 1H), 1.91 (s, 3H); LC-MS(ESI) m/z 488 (M+H)⁺.

Example 303A Step 2:3-(2-(Diphenylmethylene)hydrazinyl)-4-methylpyridine (1.3 g, 4.52 mmol)in 3 mL THF was treated with 4,4-dimethyl-3-oxopentanenitrile (850 mg,6.79 mmol) and 6N HCl (3.8 mL, 22.6 mmol). Stirred the mixture at 50° C.for 24 hours. Extracted using EtOAc/(sat.)NaHCO₃ (3×100 mL (sat.)NaHCO₃,1×100 mL brine). Dried using MgSO₄ and then purified by flashchromatography (silica, 5-100% EtOAc/Hexane) to afford3-tert-butyl-1-(4-methylpyridin-3-yl)-1H-pyrazol-5-amine (844 mg, 3.67mmol, 81%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (d, 1H), 8.40 (s, 1H), 7.38(d, 1H), 5.32 (s, 1H), 5.03 (br s, 2H), 2.08 (s, 3H), 1.20 (s, 9H);LC-MS (ESI) m/z 231 (M+H)⁺.

Example 303A Step 3:3-tert-Butyl-1-(4-methylpyridin-3-yl)-1H-pyrazol-5-amine (844 mg, 3.66mmol) was treated with phenyl chloroformate (1.90 mL, 15.0 mmol)according to the procedure in Example 118A to afford phenyl3-tert-butyl-1-(4-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (1.09 g,3.11 mmol, 85%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.09 (br s, 1H), 8.53 (d,1H), 8.43 (s, 1H), 7.44 (d, 1H), 7.39-7.34 (m, 2H), 7.22 (t, 1H), 6.98(br s, 2H), 6.35 (s, 1H), 2.09 (s, 1H), 1.27 (s, 9H); LC-MS (ESI) m/z351 (M+H)⁺.

Example 303B:3-tert-Butyl-1-(4-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (105 mg,0.30 mmol) was treated with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline(89 mg, 0.30 mmol) (prepared as described in Example 113A) using theprocedure in Example 115C to give1-(3-tert-butyl-1-(4-methylpyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(145 mg, 0.26 mmol, 87%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.02 (s, 1H),8.58-8.51 (m, 3H), 8.38 (s, 1H), 7.54-7.47 (m, 3H), 7.38-7.32 (m, 2H),7.12 (d, 1H), 6.91 (d, 1H), 6.36 (s, 1H), 3.98 (s, 6H), 2.06 (s, 3H),1.24 (s, 9H); LC-MS (ESI) m/z 554 (M+H)⁺.

Example 304 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-yl)urea

Example 304A Step 1: A stirred suspension of sodium hydride (15.6 g of a60% dispersion in mineral oil, 0.39 mol) in THF (100 mL) was heated to50° C. To this was added a mixture of ethyl2,2,3,3,3-pentafluoropropanoate (25 g, 0.13 mol) and dry acetonitrile(5.3 g, 0.13 mol), dropwise, and the resulting colorless suspension washeated at 50° C. for 4 h. After cooling to rt the reaction mixture wasconcentrated under reduced pressure and the residue poured into water(100 mL) and extracted with diethyl ether (100 mL). The aqueous layerwas separated, acidified to pH 2 with aqueous 2 M HCl and extracted withdiethyl ether (2×200 mL). The combined diethyl ether layers were driedover magnesium sulfate then concentrated under reduced pressure toafford 4,4,5,5,5-pentafluoro-3-oxopentanenitrile an orange oil (17 g)which was used in the next step without further purification.

Example 304A Step 2: A stirred mixture of4,4,5,5,5-pentafluoro-3-oxopentanenitrile (500 mg, 2.66 mmol) andphenylhydrazine hydrochloride (386 mg, 2.66 mmol) in ethanol (5 mL) washeated at 90° C. for 4 h. The reaction mixture was concentrated underreduced pressure, and the obtained oil purified by silica gel flashcolumn chromatography (eluting with a gradient of 100% petroleum etherto 10% ethyl acetate in petroleum ether) to afford3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-amine (320 mg, 43%) as a solid.¹H NMR (400 MHz, CDCl₃) δ 7.51-7.60 (m, 4H), 7.45 (m, 1H), 5.91 (s, 1H),3.96 (brs, 2H); LC-MS (ESI) m/z 278 (M+H)⁺.

Example 304A Step 3: To a stirred mixture of3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-amine (300 mg, 1.08 mmol) andpotassium carbonate (223 mg, 1.62 mmol) in THF (3 mL) at rt, was added asolution of phenyl chloroformate (169 mg, 1.08 mmol) in THF (2 mL)dropwise. After stirring for a further 15 h at rt, the reaction mixturewas filtered and the filtrate concentrated under reduced pressure togive an oil. Purification via silica gel flash column chromatography(eluting with a gradient of 100% petroleum ether to 5% ethyl acetate inpetroleum ether) afforded phenyl3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (360 mg, 84%) as asolid. ¹H NMR (400 MHz, CDCl₃) δ 7.55-7.62 (m, 5H), 7.39-7.43 (m, 2H),7.29 (m, 1H), 7.14 (m, 2H), 6.91 (m, 1H); LC-MS (ESI) m/z 398 (M+H)⁺.

Example 304B: A stirred mixture of phenyl3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (199 mg, 0.50mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as describedin Example 113A) (100 mg, 0.34 mmol), N,N-diethylisopropylamine (88 mg,0.68 mmol) in THF (1 mL) was heated at 60° C. for 15 h. After cooling tort, the reaction mixture was partitioned between saturated aqueoussodium hydrogen carbonate solution and dichloromethane. The organiclayer was separated, dried over magnesium sulfate and concentrated underreduced pressure to afford the crude product. Purification viapreparative HPLC afforded1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-yl)urea(80 mg, 39%) as a colorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (s,1H), 8.82 (s, 1H), 8.54 (s, 1H), 7.55-7.61 (m, 7H), 7.36-7.40 (m, 2H),7.18 (m, 1H), 6.95 (m, 1H), 6.88 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H);LC-MS (ESI) m/z 601 (M+H)⁺.

Example 305 Preparation of1-(3-tert-butyl-1-(2-methylpyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 305A Step 1: 3-Bromo-2-methyl-pyridine (1.0 g, 5.80 mmol) in 15mL dry toluene was treated with benzophenone hydrazone (1.25 g, 6.39mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (170 mg, 0.29mmol), sodium tert-butoxide (835 mg, 8.70 mmol), and Pd(II)(OAc)₂ (67mg, 0.30 mmol). Heated to 120° C. in the microwave for five minutes.Extracted using EtOAc/H₂O (3×100 mL EtOAc, 1×100 mL H₂O, 1×100 mLbrine). Dried using Na₂SO₄ and then purified by flash chromatography(silica, 10-50% EtOAc/Hexane) to afford3-(2-(diphenylmethylene)hydrazinyl)-2-methylpyridine (1.25 g, 4.35 mmol,75%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.95 (d, 1H), 7.85 (d, 1H), 7.70-7.53(m, 6H), 7.45-7.34 (m, 5H), 7.20 (d, 1H), 2.07 (s, 3H); LC-MS (ESI) m/z288 (M+H)⁺.

Example 305A Step 2:3-(2-(Diphenylmethylene)hydrazinyl)-2-methylpyridine (1.25 g, 4.35 mmol)was treated with 4,4-dimethyl-3-oxopentanenitrile (810 mg, 6.50 mmol)and 6N HCl (3.6 mL, 22.0 mmol) according to the procedure described forExample 303A Step 2. Purification by flash chromatography (silica, 0-10%MeOH/DCM) afforded3-tert-butyl-1-(2-methylpyridin-3-yl)-1H-pyrazol-5-amine (679 mg, 2.95mmol, 68%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (d, 1H), 7.67 (d, 1H), 7.33(d, 1H), 5.31 (s, 1H), 5.00 (br s, 2H), 2.23 (s, 3H), 1.21 (s, 9H);LC-MS (ESI) m/z 231 (M+H)⁺.

Example 305A Step 3: Following the procedure in Example 118A,3-tert-butyl-1-(2-methylpyridin-3-yl)-1H-pyrazol-5-amine (679 mg, 2.94mmol) was treated with phenyl chloroformate (1.50 mL, 12.0 mmol) toafford phenyl3-tert-butyl-1-(2-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (722 mg,2.06 mmol, 70%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.24 (br s, 1H), 8.71 (s,1H), 8.07 (d, 1H), 7.68 (br s, 1H), 7.41-7.36 (m, 2H), 7.23 (t, 1H),7.04 (br s, 2H), 6.37 (s, 1H), 2.36 (s, 3H), 1.28 (s, 9H); LC-MS (ESI)m/z 351 (M+H)⁺.

Example 305B: Phenyl3-tert-butyl-1-(2-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (105 mg,0.3 mmol) was treated with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline(89 mg, 0.30 mmol) (prepared as described in Example 113A) using theprocedure in Example 115C to afford1-(3-tert-butyl-1-(2-methylpyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(33 mg, 0.06 mmol, 20%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.60(d, 1H), 8.54 (s, 1H), 8.35 (s, 1H), 7.80 (d, 1H), 7.54 (s, 2H),7.45-7.32 (m, 3H), 7.12 (d, 1H), 6.91 (d, 1H), 6.35 (s, 1H), 3.99 (s,3H), 3.97 (s, 3H), 2.20 (s, 3H) 1.25 (s, 9H); LC-MS (ESI) m/z 554(M+H)⁺.

Example 306 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)urea

Example 306A: To a solution of1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (590mg, 2.2 mmol) and potassium carbonate (304 mg, 2.85 mmol) in anhydrousDCM (5.2 ml) was added dropwise phenyl chloroformate (0.30 ml, 2.4 mmol)as a solution in DCM (2.5 ml). The reaction mixture was stirred at rtovernight, then filtered and concentrated under reduced pressure. Thecrude was purified by silica gel chromatography (hexane/ethyl acetate35%) to afford phenyl1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-ylcarbamate(748 mg, 87%) as a solid. ¹H NMR (300 MHz, CDCl₃) δ 1.60 (s, 6H), 6.65(brs, 1H), 7.02-7.55 (m, 11H); LC-MS (ESI) m/z 390 (M+H)⁺.

Example 306B: To a solution of3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol), preparedas described in Example 113A, in THF (3.3 ml) was added DMAP (20 mg,0.16 mmol) and phenyl1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-ylcarbamate(104 mg, 0.3 mmol) described in the previous step. The reaction mixturewas stirred at rt overnight, then concentrated under reduced pressure.The crude was purified by silica gel chromatography (hexane/ethylacetate 25-100%) and triturated in diethyl ether to afford1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-O-1H-pyrazol-5-yl)urea(103 mg, 62%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.56 (s, 6H), 4.02(s, 6H), 6.55 (s, 1H), 6.94 (d, J=9 Hz, 1H), 7.17 (d, J=9 Hz, 1H),7.34-7.57 (m, 9H), 8.55-8.59 (m, 2H), 9.28 (s, 1H); LC-MS (ESI) m/z 593(M+H)⁺.

Example 307 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)urea

Using the procedure described in Example 306B, to a solution of3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), preparedas described in Example 115B, in THF (3 ml) was added DMAP (23 mg, 0.18mmol) and phenyl1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-ylcarbamate(117 mg, 0.3 mmol) described in Example 306A to afford1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)urea(109 mg, 60%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.57 (s, 6H), 4.04(s, 6H), 6.55 (s, 1H), 7.25 (d, J=6 Hz, 1H), 7.33-7.49 (m, 5H),7.55-7.60 (m, 4H), 7.80 (s, 1H), 8.59 (s, 1H), 8.69 (s, 1H), 9.29 (s,1H); LC-MS (ESI) m/z 609 (M+H)⁺.

Example 308 Preparation of1-(3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 308A Step 1: To a solution of 2,2-dimethyl-3-oxopentanedinitrile(500 mg, 3.7 mmol) prepared as described in Example 125A Step 1, inanhydrous EtOH (33 ml) was added phenylhydrazine hydrochloride (763 mg,3.7 mmol) and the reaction mixture was heated at 60° C. for 2 h. Thesolvent was removed under reduced pressure and the residue taken inEtOAc, washed with water and brine and the organics combined, dried(MgSO₄) and concentrated. The residue was purified by silica gelchromatography (hexane/ethyl acetate 1:1) to afford2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropanenitrile (451 mg,54%) as a solid. ¹H NMR (300 MHz, CDCl₃) δ 1.76 (s, 6H), 3.84 (brs, 2H),5.69 (s, 1H), 7.26-7.57 (m, 5H); LC-MS (ESI) m/z 227 (M+H)⁺.

Example 308A Step 2: Using the procedure described in Example 306A, to asolution of 2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropanenitrile(451 mg, 2 mmol) and potassium carbonate (359 mg, 2.6 mmol) in anhydrousDCM (4 ml) was added dropwise phenyl chloroformate (0.28 ml, 2.2 mmol)as a solution in DCM (2 ml) to afford phenyl3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate (527 mg, 76%).¹H NMR (300 MHz, CDCl₃) δ 1.74 (s, 6H), 6.66 (s, 1H), 7.05-7.60 (m,11H); LC-MS (ESI) m/z 347 (M+H)⁺.

Example 308B: Using the procedure described in Example 306B, to asolution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3mmol), prepared as described in Example 113A, in THF (3.3 ml) was addedDMAP (20 mg, 0.16 mmol) and phenyl3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate (104 mg, 0.3mmol) described in the previous step to afford1-(3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(77.6 mg, 42%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.72 (s, 6H),3.99 (s, 6H), 6.57 (s, 1H), 6.94 (d, J=6 Hz, 1H), 7.18 (d, J=6.6 Hz,1H), 7.17-7.20 (m, 2H), 7.35-7.56 (m, 7H), 8.56 (s, 1H), 8.64 (s, 1H),9.28 (s, 1H); LC-MS (ESI) m/z 550 (M+H)⁺.

Example 309 Preparation of1-(3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

Using the procedure described in Example 306B, to a solution of3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), preparedas described in Example 115B, in THF (3.3 ml) was added DMAP (20 mg,0.16 mmol) and phenyl3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate (104 mg, 0.3mmol) described in Example 308A to afford1-(3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(68.87 mg, 40%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.74 (s, 6H),4.04 (s, 6H), 6.58 (s, 1H), 7.26-7.86 (m, 10H), 8.63-8.69 (m, 2H), 9.28(s, 1H); LC-MS (ESI) m/z 609 (M+H)⁺.

Example 310 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(3-(2-chloro-6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

To a stirred solution of1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (prepared asdescribed in Example 1A) (80 mg, 0.291 mmol) in anhydrous degassed DMF(2 mL) at rt and under an argon atmosphere, was added potassiumtert-butoxide (65 mg, 0.581 mmol). The reaction mixture was stirred atrt for a further 2 h. A solution of2,4-dichloro-6,7-dimethoxyquinazoline (75 mg, 0.291 mmol) in anhydrousDMF (1 mL) was added and the reaction mixture was stirred at rt for afurther 15 h. The reaction mixture was partitioned between a mixture ofethyl acetate (20 mL) and brine solution (20 mL), and the organic layerseparated. The aqueous layer was extracted further with ethyl acetate(1×20 mL) and the combined organic layers dried over magnesium sulfate.Concentration under reduced pressure gave the crude product which waspurified via silica gel flash chromatography (eluting with a gradient of25% ethyl acetate in hexanes to 100% ethyl acetate) to afford1-(5-tert-butylisoxazol-3-yl)-3-(3-(2-chloro-6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(46 mg, 32%) as a solid. ¹H NMR (300 MHz, CDCl₃) δ 9.60 (brs, 1H), 9.03(brs, 1H), 7.61 (m, 1H), 7.57 (m, 1H), 7.39-7.46 (m, 2H), 7.31 (m, 1H),7.01 (m, 1H), 6.48 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 1.28 (s, 9H);LC-MS (ESI) m/z 498 (M+H)+.

Example 311 Preparation of 1-(3-(1,1-difluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 311A Step 1: 3-Hydrazinopyridine hydrochloride (435 mg, 3.0mmol) was treated with 4,4-difluoro-3-oxopentanenitrile (400 mg, 3.0mmol) (prepared as described in Example 152A Step 1) according to theprocedure in Example 161A Step 3 to afford3-(1,1-difluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-5-amine (62 mg, 0.27mmol, 9%). ¹H NMR (300 MHz, MeOD) δ 8.86 (s, 1H), 8.60 (d, 1H), 8.12 (d,1H), 7.62 (t, 1H), 5.82 (s, 1H), 1.92 (t, 3H); LC-MS (ESI) m/z 225(M+H)⁺.

Example 311A Step 2: Following the procedure in Example 118A,3-(1,1-difluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-5-amine (60 mg, 0.27mmol) was treated with phenyl chloroformate (0.13 mL, 1.07 mmol) toafford phenyl3-(1,1-difluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate (27 mg,0.078 mmol, 30%). ¹H NMR (300 MHz, MeOD) δ 8.90 (s, 1H), 8.70 (s, 1H),8.15 (d, 1H), 7.69 (d, 1H), 7.44-7.12 (m, 5H), 4.87 (s, 3H); LC-MS (ESI)m/z 345 (M+H)⁺.

Example 311B: Following the procedure in Example 115C, phenyl3-(1,1-difluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate (27 mg,0.078 mmol) was treated with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline(26 mg, 0.086 mmol) (prepared as described in Example 113A) to afford1-(3-(1,1-difluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(27 mg, 0.049 mmol, 63%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.23 (s, 1H),8.82-8.78 (m, 2H), 8.70 (d, 1H), 8.54 (s, 1H), 8.04 (d, 1H), 7.65-7.61(m, 2H), 7.54-7.51 (m, 2H), 7.19 (d, 1H), 6.93 (d, 1H), 6.69 (s, 1H),3.99 (s, 6H), 2.00 (t, 3H); LC-MS (ESI) m/z 548 (M+H)⁺.

Example 312 Preparation of1-(3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 312A Step 1: Using the procedure described in Example 308A Step1, to a solution of 4,4-dimethyl-3-oxopentanenitrile (782 mg, 6.25 mmol)in anhydrous EtOH (30 ml) was added 5-hydrazinyl-2-methylpyridine (1 g,8.12 mmol) and the reaction mixture was heated at 80° C. overnight. Theresidue was purified by silica gel chromatography (DCM/EtOAc 10-50%) toafford 3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-amine (95 mg,7%). ¹H NMR (300 MHz, CDCl₃) δ 1.34 (s, 9H), 2.59 (s, 3H), 3.67 (brs,2H), 5.56 (s, 1H), 7.25 (d, J=9 Hz, 1H), 7.81 (d, J=9 Hz, 1H), 8.74 (s,1H); LC-MS (ESI) m/z 231 (M+H)⁺.

Example 312A Step 2: Using the procedure described in Example 306A, to asolution of 3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-amine (95mg, 0.41 mmol) and potassium carbonate (75 mg, 0.54 mmol) in anhydrousDCM (1.5 ml) was added dropwise phenyl chloroformate (0.16 ml, 1.24mmol) as a solution in DCM (1 ml). The crude was purified by silica gelchromatography (DCM/EtOAc 7-60%) to afford phenyl3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (61 mg,42%). ¹H NMR (300 MHz, CDCl₃) δ 1.34 (s, 9H), 2.63 (s, 3H), 6.47 (s,1H), 6.83 (d, J=8 Hz, 1H), 6.91-6.93 (m, 3H), 7.12 (s, 1H), 7.21-7.40(m, 2H), 7.78 (d, J=8 Hz, 1H), 8.68 (d, J=2 Hz, 1H); LC-MS (ESI) m/z 351(M+H)⁺.

Example 312B: Using the procedure described in Example 306B, to asolution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (54 mg, 0.18mmol), prepared as described in Example 113A, in THF (2 ml) was addedDMAP (20 mg, 0.16 mmol) and phenyl3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (62 mg,0.18 mmol), described in the previous step, to afford1-(3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(59 mg, 60%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.26 (s, 9H), 2.53(s, 3H), 3.98 (s, 6H), 6.37 (s, 1H), 6.92 (d, J=7.8 Hz, 1H), 7.18 (d,J=8.4 Hz, 1H), 7.36-7.43 (m, 3H), 7.54-7.55 (m, 2H), 7.83 (d, J=8.4 Hz,1H), 8.51 (s, 1H), 8.55 (s, 1H), 8.61 (d, J=3 Hz, 1H), 9.18 (s, 1H);LC-MS (ESI) m/z 554 (M+H)⁺.

Example 313 Preparation of1-(3-tert-butyl-1-(2-oxo-1,2-dihydropyridin-4-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 313A Step 1: To a solution of hydrazine (8 mL) in DME (40 mL)was added dihydroxypyridine (2.00 g, 18 mmol) and the reaction heated atreflux overnight. The solution was cooled to rt, and the solids removedby filtration. The filtrate was concentrated and the resulting solidcrystallized from hot EtOH to afford 4-hydrazinylpyridin-2(1H)-one (1.75g, 78% yield). LC-MS (ESI) m/z 126 (M+H)⁺.

Example 313A Step 2: Following the procedure for Example 282A Step1,4-hydrazinylpyridin-2(1H)-one was heated at 80° C. overnight with4,4-dimethyl-3-oxopentanenitrile. The reaction mixture was concentrated,triturated with DCM, and purified using silica gel chromatographyeluting with a MeOH/DCM gradient (2-10%) to afford4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)pyridin-2(1H)-one (307 mg, 33%yield). ¹H NMR (300 MHz, DMSO d₆) δ 1.18 (s, 9H), 5.43 (s, 1H), 5.47 (s,2H), 6.55 (s, 1H), 6.66 (m, 1H), 7.37 (d, 1H), 11.40 (s, 1H); LC-MS(ESI) m/z 233 (M+H)⁺

Example 313A Step 3: Following the procedure for Example 282A Step 2,substituting 4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)pyridin-2(1H)-onefor 3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-amine and reactingwith phenyl chloroformate. Purification using silica gel chromatographyeluting with EtOAC/hexane (12-100%) to afford phenyl3-tert-butyl-1-(2-oxo-1,2-dihydropyridin-4-yl)-1H-pyrazol-5-ylcarbamate(100 mg, 21% yield). ¹H NMR (300 MHz, DMSO d₆) δ 1.30 (s, 9H), 5.50 (s,1H), 5.72 (s, 2H), 7.41 (m, 4H), 7.52 (m, 3H), 7.74 (s, 1H), 8.45 (d,1H); LC-MS (ESI) m/z 353 (M+H)⁺

Example 313B: The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (75 mg, 0.25 mmol) and thecarbamate from the previous step (100 mg, 0.28 mmol) using the procedurein Example 115C to give1-(3-tert-butyl-1-(2-oxo-1,2-dihydropyridin-4-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(107 mg, 0.20 mmol, 79%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.64 (br s, 1H),9.35 (s, 1H), 8.65 (br s, 1H), 8.56 (s, 1H), 7.57 (s, 1H), 7.56 (s, 1H),7.48 (d, 1H), 7.42-7.35 (m, 2H), 7.25 (d, 1H), 6.94 (d, 1H), 6.57 (d,1H), 6.50 (s, 1H), 6.39 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 1.26 (s,9H); LC-MS (ESI) m/z 556 (M+H)⁺.

Example 314 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(1-(5-fluoropyridin-3-yl)-3-isopropyl-1H-pyrazol-5-yl)urea

Example 314A Step 1: In degassed, dry toluene (35 mL)5-bromo-5-fluoropyridine (2.29 g, 13 mmol), benzophenone hydrazide (2.80g, 14.3 mmol), sodium tert-butoxide (1.90 g, 19.8 mmol), palladiumacetate (292 mg, 1.3 mmol), and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (752 mg, 1.3 mmol) wereadded and the reaction mixture heated at 85° C. overnight. The mixturewas cooled to rt and partitioned between EtOAc/water and extractedtwice. The combined extracts were washed with brine and dried overmagnesium sulfate, filtered and concentrated. The resulting residue waspurified using silica gel chromatography eluting with 12-100%EtOAc/hexanes to afford3-(2-(diphenylmethylene)hydrazinyl)-5-fluoropyridine (3.28 g, 86%yield). ¹H NMR (300 MHz, DMSO d₆) δ 7.34 (m, 5H), 7.54 (m, 3H), 7.63 (m,3H), 7.94 (m, 1H), 8.40 (m, 1H), 9.38 (s, 1H); LC-MS (ESI) m/z 292(M+H)⁺

Example 314A Step 2: To a solution 4-methyl-3-oxopentanenitrile (333 mg,3 mmol) and 3-(2-(diphenylmethylene)hydrazinyl)-5-fluoropyridine (580mg, 2 mmol) in THF (10 mL) was added 6 M HCl (1.8 mL) and the solutionheated to 50° C. overnight. The solution was then cooled to rt,concentrated and partitioned between DCM and water, the aqueous layerdecanted, and the organics concentrated. The residue was purified usingsilica gel chromatography eluting with EtOAc/hexane (12-100%) followedby a MeOH/DCM flush (10%) to elute1-(5-fluoropyridin-3-yl)-3-isopropyl-1H-pyrazol-5-amine. LC-MS (ESI) m/z221 (M+H)⁺

Example 314A Step 3: Following the procedure for Example 282A Step2,1-(5-fluoropyridin-3-yl)-3-isopropyl-1H-pyrazol-5-amine was treatedwith phenyl chloroformate. Purification using silica gel chromatographyeluting with MeOH/DCM (0-10%) afforded phenyl1-(5-fluoropyridin-3-yl)-3-isopropyl-1H-pyrazol-5-ylcarbamate (235 mg,35% yield) for steps B and C. ¹H NMR (300 MHz, DMSO d₆) δ 1.25 (s, 6H),2.93 (m, 1H), 6.40 (s, 1H), 7.15 (bs, 2H), 7.29 (m, 2H), 7.42 (m, 3H),8.00 (m, 1H), 8.65 (s, 1H), 8.72 (s, 1H), 10.32 (s, 1H); LC-MS (ESI) m/z341 (M+H)⁺

Example 314B: The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (75 mg, 0.25 mmol) and thecarbamate from the previous step (102 mg, 0.3 mmol) using the procedurein Example 115C to give1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(1-(5-fluoropyridin-3-O-3-isopropyl-1H-pyrazol-5-yl)urea(121 mg, 0.22 mmol, 89%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.22 (s, 1H), 8.71(s, 1H), 8.68 (s, 1H), 8.62 (d, 1H), 8.55 (s, 1H), 8.00 (t, 1H), 7.97(t, 1H), 7.55 (s, 1H), 7.52 (t, 1H), 7.39 (s, 1H), 7.37 (t, 1H), 7.21(d, 1H), 6.93 (d, 1H), 6.38 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 2.90(septet, 1H), 1.22 (d, 6H); LC-MS (ESI) m/z 544 (M+H)⁺.

Example 315 Preparation of1-(3-(1,1-difluoroethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 315A Step 1: Following the procedure for Example 282A Step 1,substituting p-methoxyphenylhydrazine for 2,4-dimethylphenylhydrazinehydrochloride and 4,4-difluoro-3-oxopentanenitrile was substituted for4,4-Dimethyl-3-oxopentanenitrile. Concentration and purification usingsilica gel chromatography eluting with EtOAc/hexanes (5-40%) afforded3-(1,1-difluoroethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-amine in 11%yield. LC-MS (ESI) m/z 254 (M+H)⁺.

Example 315A Step 2:3-(1,1-difluoroethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-amine wasconverted to the phenyl carbamate using the procedure for Example 282AStep 2. Purification using silica gel chromatography eluting withEtOAc/hexane (5-40%) afforded phenyl3-(1,1-difluoroethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-ylcarbamate in64% yield. LC-MS (ESI) m/z 374 (M−H)⁻

Example 315B: The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (45 mg, 0.15 mmol) and thecarbamate from the previous step (75 mg, 0.2 mmol) using the procedurein Example 115C to give1-(3-(1,1-difluoroethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(40 mg, 0.07 mmol, 46%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (s, 1H), 8.56(s, 1H), 8.55 (s, 1H), 7.55 (s, 1H), 7.54 (s, 1H), 7.46 (d, 2H), 7.39(s, 1H), 7.38 (t, 1H), 7.18 (d, 1H), 7.13 (d, 2H), 6.94 (d, 1H), 6.62(s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 3.84 (s, 3H), 1.98 (s, 3H); LC-MS(ESI) m/z 577 (M+H)⁺.

Example 316 Preparation of1-(3-(1,1-difluoroethyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 316A Step 1: Following the procedure for Example 314A Step 2,substituting 4,4-difluoro-3-oxopentanenitrile for4-methyl-3-oxopentanenitrile and increasing the temperature to 75° C.,3-(1,1-difluoroethyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-amine wasisolated by silica gel chromatography eluting with an EtOAC/hexanegradient (5-75%) to give 52% yield. LC-MS (ESI) m/z 243 (M+H)⁺

Example 316A Step 2: The phenyl carbamate of3-(1,1-difluoroethyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-amine wasprepared using the procedure found in Example 315A Step 2. Aftertrituration with DCM, phenyl3-(1,1-difluoroethyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-ylcarbamatewas isolated in 73% yield. LC-MS (ESI) m/z 363 (M−H)⁻

Example 316B: The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (75 mg, 0.25 mmol) and thecarbamate from the previous step (108 mg, 0.3 mmol) using the procedurein Example 115C to give 1-(3-(1,1-difluoroethyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(40 mg, 0.07 mmol, 28%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 8.92(s, 1H), 8.76 (s, 1H), 8.75 (s, 1H), 8.56 (s, 1H), 8.15 (t, 1H), 8.12(t, 1H), 7.55 (s, 1H), 7.52 (t, 1H), 7.42-7.35 (m, 2H), 7.22 (d, 1H),6.95 (d, 1H), 6.71 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 2.01 (t, 3H);LC-MS (ESI) m/z 566 (M+H)⁺.

Example 317 Preparation of1-(3-tert-butyl-1-(6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 317A Step 1: 5-Bromo-2(1H)-pyridone (2.0 g, 11.5 mmol) in 25 mLdry toluene was treated with benzophenone hydrazone (2.50 g, 12.7 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (200 mg, 0.345 mmol),and sodium tert-butoxide (2.2 g, 23 mmol). The mixture was degassed withargon for 15 minutes. Added Pd(II)(OAc)₂ (80 mg, 0.345 mmol) and stirredat 90° C. for 16 hours. Extracted using EtOAc/H₂O (3×150 mL EtOAc, 1×150mL brine). Dried using Na₂SO₄ and then purified by flash chromatography(silica, 0-12% MeOH/DCM) to afford5-(2-(diphenylmethylene)hydrazinyl)pyridin-2(1H)-one (950 mg, 3.28 mmol,29%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.12 (s, 1H), 8.49 (s, 1H), 7.61-7.25(m, 12H), 6.31 (d, 1H); LC-MS (ESI) m/z 290 (M+H)⁺.

Example 317A Step 2:5-(2-(Diphenylmethylene)hydrazinyl)pyridin-2(1H)-one (950 mg, 3.29 mmol)was treated with 4,4-dimethyl-3-oxopentanenitrile (620 mg, 4.93 mmol)and 6N HCl (2.70 mL, 16.4 mmol) according to the procedure in Example303A Step 2. Purification by flash chromatography (silica, 1-8%MeOH/DCM) afforded5-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)pyridin-2(1H)-one (46 mg, 0.20mmol, 6%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.65 (br s, 1H), 7.55-7.51 (m,2H), 6.39 (d, 1H), 5.29 (s, 1H), 5.11 (s, 2H), 1.21 (s, 9H); LC-MS (ESI)m/z 233 (M+H)⁺.

Example 317A Step 3: Following the procedure in Example 118A,5-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)pyridin-2(1H)-one (46 mg, 0.19mmol) was treated with phenyl chloroformate (0.10 mL, 0.79 mmol) toafford phenyl3-tert-butyl-1-(6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazol-5-ylcarbamate(8 mg, 0.023 mmol, 12%). ¹H NMR (300 MHz, MeOD) δ 7.68 (d, 2H), 7.38 (t,2H), 7.23 (t, 1H), 7.09 (br s, 2H), 6.63 (d, 1H), 6.34 (s, 1H), 1.30 (s,9H); LC-MS (ESI) m/z 353 (M+H)⁺.

Example 317B: Following the procedure in Example 115C, phenyl3-tert-butyl-1-(6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazol-5-ylcarbamate(8 mg, 0.0227 mmol) was treated with3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (8 mg, 0.025 mmol) (preparedas described in Example 113A) to afford1-(3-tert-butyl-1-(6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(7.8 mg, 0.014 mmol, 62%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.1 (br s, 1H),9.03 (br s, 1H), 8.56 (br s, 2H), 7.53-7.26 (m, 7H), 6.91 (d, 1H),6.43-6.35 (m, 2H), 4.05 (s, 6H), 1.22 (s, 9H); LC-MS (ESI) m/z 556(M+H)⁺.

Example 318 Preparation of1-(3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 318A Step 1: A stirred mixture of4,4-difluoro-3-oxopentanenitrile (prepared as described in Example 152AStep 1) (1 g, 7.52 mmol) and phenyl hydrazine hydrochloride (1.08 g,7.52 mmol) in ethanol (30 mL) was heated at 70° C. for 8 h. Aftercooling to rt, the mixture was concentrated under reduced pressure. Theresidue was partitioned between dichloromethane (200 mL) and saturatedaqueous sodium hydrogen carbonate solution (200 mL). The organic layerwas separated and dried over magnesium sulfate and filtered.Concentration under reduced pressure gave an oil, which was purified viasilica gel column chromatography (eluting with a gradient of 5% to 65%ethyl acetate in hexanes) to afford3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-amine (528 mg, 31%) as ayellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.36-7.57 (m, 5H), 5.81 (s, 1H),3.84 (brs, 2H), 2.01 (t, J=18 Hz, 3H); LC-MS (ESI) m/z 224 (M+H)⁺.

Example 318A Step 2: A mixture of3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-amine (528 mg, 2.37 mmol),potassium carbonate (979 mg, 7.10 mmol) and phenyl chloroformate (556mg, 3.55 mmol) in anhydrous dichloromethane (20 mL) was stirred at rtfor 15 h. Additional phenyl chloroformate (556 mg, 3.55 mmol) andpotassium carbonate (979 mg, 7.10 mmol) was added and the mixturestirred for a further 4 h. The mixture was concentrated under reducedpressure and the residue partitioned between ethyl acetate and saturatedaqueous sodium hydrogen carbonate solution. The organic layer wasseparated, washed with water, saturated aqueous sodium hydrogencarbonate solution, then dried over magnesium sulfate and filtered.Concentration under reduced pressure gave an oil which was purified viasilica gel column chromatography (eluting with a gradient of 12% ethylacetate in hexanes to 100% ethyl acetate) to afford phenyl3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (400 mg, 49%) asan oil. ¹H NMR (300 MHz, CDCl₃) δ 7.51-7.58 (m, 5H), 7.35-7.41 (m, 2H),7.26 (m, 1H), 7.15 (m, 2H), 7.00 (brs, 1H), 6.80 (s, 1H), 2.04 (t, J=18Hz, 3H); LC-MS (ESI) m/z 344 (M+H)⁺.

Example 318B: Using the procedure described in Example 306B, to asolution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3mmol), prepared as described in Example 113A, in THF (3.3 ml) was addedDMAP (20 mg, 0.16 mmol) and phenyl3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (103 mg, 0.3mmol), described in the previous step. The crude was purified by silicagel chromatography (DCM/MeOH 0-15%) and triturated in diethyl ether toafford1-(3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(102 mg, 62%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.99 (t, J=18 Hz,3H), 3.99 (s, 6H), 6.66 (s, 1H), 6.94 (d, J=9.6 Hz, 1H), 7.18 (d, J=9.6Hz, 1H), 7.35-7.40 (m, 2H), 7.51-7.60 (m, 7H), 8.55 (s, 1H), 8.66 (s,1H), 9.26 (s, 1H); LC-MS (ESI) m/z 547 (M+H)⁺.

Example 319 Preparation of 1-(3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

Using the procedure described in Example 306B, to a solution of3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), preparedas described in Example 115B, in THF (3.3 ml) was added DMAP (20 mg,0.16 mmol) and phenyl3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (103 mg, 0.3mmol), described in Example 318A. The crude was purified by silica gelchromatography (DCM/MeOH 0-15%) and triturated in diethyl ether toafford1-(3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(127 mg, 75%) as a solid. ¹HNMR (300 MHz, DMSO-d₆) δ 1.99 (t, J=18 Hz,3H), 3.99 (s, 6H), 6.67 (s, 1H), 7.25 (d, J=7.2 Hz, 1H), 7.34 (d, J=5Hz, 2H), 7.38-7.59 (m, 7H), 7.77 (s, 1H), 8.66 (s, 1H), 8.68 (s, 1H),9.27 (s, 1H); LC-MS (ESI) m/z 563 (M+H)⁺.

Example 320 Preparation of1-(3-tert-butyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 320A Step 1: To a solution of 4-bromo-2-methylpyridine (0.7 ml,5.81 mmol) in anhydrous toluene, previously degassed with Ar, were addedbenzophenone hydrazone (1.25 g, 6.4 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (336 mg, 0.58 mmol),palladium (II) acetate (130 mg, 0.581 mmol), and sodium tert-butoxide(838 mg, 8.72 mmol). The reaction mixture was sealed and stirred at 85°C. overnight, then filtered through celite, washed with DCM andconcentrated under reduced pressure. The residue was taken in EtOAc,washed with water, extracted, and the organics were combined and dried(MgSO₄). The crude was purified by silica gel chromatography(hexane/ethyl acetate 10-100%) to afford542-(diphenylmethylene)hydrazinyl)-2-methylpyridine (1.6 g, 95%). ¹H NMR(300 MHz, CDCl₃) δ 2.47 (s, 3H), 6.76 (d, J=2 Hz, 1H), 6.83 (s, 1H),7.31-7.36 (m, 5H), 7.53-7.63 (m, 6H), 8.20 (d, J=6 Hz, 1H); LC-MS (ESI)m/z 288 (M+H)⁺.

Example 320A Step 2: To a solution of542-(diphenylmethylene)hydrazinyl)-2-methylpyridine (500 mg, 1.74 mmol),from the previous step, in anhydrous THF (4 ml) were added4,4-dimethyl-3-oxopentanenitrile (327 mg, 2.61 mmol) and a 6N solutionof hydrogen chloride (0.26 ml) dropwise. The reaction mixture wasstirred at 50° C. overnight. The solvent was removed under reducedpressure and the residue purified by silica gel chromatography (DCM/MeOH0-10%) to afford3-tert-butyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-5-amine (350 mg, 87%).¹H NMR (300 MHz, CDCl₃) δ 1.30 (s, 9H), 2.48 (s, 3H), 3.82 (brs, 2H),5.57 (s, 1H), 7.45 (d, J=6 Hz, 1H), 7.46 (s, 1H), 8.51 (d, J=6 Hz, 1H);LC-MS (ESI) m/z 231 (M+H)⁺.

Example 320A Step 3: Using the procedure described in Example 306A, to asolution of 3-tert-butyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-5-amine(496 mg, 2.2 mmol), from the previous step, and potassium carbonate (395mg, 2.9 mmol) in anhydrous DCM (8 ml) was added dropwise phenylchloroformate (0.83 ml, 6.6 mmol) as a solution in DCM (5 ml). The crudewas purified by silica gel chromatography (DCM/MeOH 0-10%) to affordphenyl 3-tert-butyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-5-ylcarbamate(130 mg, 17%). ¹H NMR (300 MHz, CDCl₃) δ 1.27 (s, 9H), 2.54 (s, 3H),6.45 (s, 1H), 6.81 (d, J=8 Hz, 1H), 7.12-7.28 (m, 5H), 7.29-7.43 (m, 2H)8.49 (d, J=6 Hz, 1H); LC-MS (ESI) m/z 351 (M+H)⁺.

Example 320B: Using the procedure described in Example 306B, to asolution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (88 mg, 0.29mmol), prepared as described in Example 113A, in THF (2 ml) was addedDMAP (20 mg, 0.16 mmol) and3-tert-butyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-5-ylcarbamate (130 mg,0.37 mmol) described in the previous step. The crude was purified bysilica gel chromatography (DCM/MeOH 0-10%) to afford1-(3-tert-butyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(63 mg, 39%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.27 (s, 9H), 2.49(s, 3H), 3.98 (s, 6H), 6.40 (s, 1H), 6.95 (d, J=7.8 Hz, 1H), 7.22 (d,J=7.8 Hz, 1H), 7.39-7.44 (m, 3H), 7.45-7.55 (m, 3H), 8.49 (d, J=6 Hz,1H), 8.52 (s, 1H), 8.66 (s, 1H), 9.27 (s, 1H); LC-MS (ESI) m/z 554(M+H)⁺.

Example 321 Preparation of1-(3-tert-butyl-1-ethyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

Example 321A Step 1: A stirred solution of ethylhydrazine oxalate (1.0g, 6.66 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 7.98 mmol) inethanol (5 mL) was refluxed for 15 h. After cooling to rt, the reactionmixture was concentrated under reduced pressure and the obtained crudeproduct was recrystallized from a mixture of diethyl ether and petroleumether to afford 3-tert-butyl-1-ethyl-1H-pyrazol-5-amine oxalate (0.8 g,47%) as colorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ 5.15 (s, 1H), 3.82(q, J=7.2 Hz, 2H), 1.02-1.19 (m, 12H); LC-MS (ESI) m/z 168 (M+H)⁺.

Example 321A Step 2: To a stirred mixture of3-tert-butyl-1-ethyl-1H-pyrazol-5-amine oxalate (350 mg, 1.36 mmol),potassium carbonate (280 mg, 2 mmol) and N,N-diisopropylethylamine (170mg, 1.3 mmol) in dichloromethane (3 mL) at rt, was added dropwise,phenyl chloroformate (220 mg, 1.4 mmol) and the reaction mixture wasstirred for a further 3 h. The reaction mixture was filtrated, thefiltrate concentrated under reduced pressure and the residue partitionedbetween dichloromethane and water. The organic layer was separated andwashed with brine, then concentrated under reduced pressure to give asolid which was recrystallized from diethyl ether to afford phenyl3-tert-butyl-1-ethyl-1H-pyrazol-5-ylcarbamate (300 mg, 77%) as acolorless solid. LC-MS (ESI) m/z 288 (M+H)⁺.

Example 321B: A stirred solution of phenyl3-tert-butyl-1-ethyl-1H-pyrazol-5-ylcarbamate (150 mg, 0.523 mmol),N,N-diisopropylethylamine (80 mg, 0.62 mmol) and3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described inExample 115B) (100 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60° C.for 15 h. After cooling to rt, the reaction solution was partitionedbetween dichloromethane and a saturated aqueous solution of sodiumcarbonate. The organic phase was separated and concentrated underreduced pressure. The crude product was purified via silica gel columnchromatography (eluting with a gradient of 40:1 to 20:1dichloromethane:methanol) then reverse-phase preparative HPLC to afford1-(3-tert-butyl-1-ethyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(30 mg, 19%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.12(s, 1H), 8.70 (s, 1H), 8.53 (s, 1H), 7.85 (s, 1H), 7.52 (m, 1H), 7.43(m, 1H), 7.35-7.36 (m, 2H), 7.25 (m, 1H), 6.04 (s, 1H), 4.00 (s, 6H),3.93 (m, 2H), 1.21-1.29 (m, 12H); LC-MS (ESI) m/z 507 (M+H)⁺.

Example 322 Preparation of1-(3-tert-butyl-1-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 322A Step 1: Following the procedure in Example 161A Step3,3-hydrazinylpyridine (501 mg, 4.0 mmol) and4,4-dimethyl-3-oxopentanenitrile (437 mg, 4.0 mmol) were reacted to give3-tert-butyl-1-(pyridin-3-yl)-1H-pyrazol-5-amine (667 mg, 3.09 mmol,77%), LC-MS (ESI) m/z 217 (M+H)⁺.

Example 322A Step 2: Following the procedure in Example 118A,3-tert-butyl-1-(pyridin-3-yl)-1H-pyrazol-5-amine (665 mg, 3.08 mmol) andphenyl chloroformate (705 mg, 4.5 mmol) were reacted to give phenyl3-tert-butyl-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate (984 mg, 2.93mmol, 95%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.42-7.39 (m, 3H), 7.30-7.26 (m,5H), 6.85 (t, 1H), 6.82 (d, 2H), 1.21 (s, 9H); LC-MS (ESI) m/z 337(M+H)⁺.

Example 322B: The title compound was prepared from the carbamate in theprevious step (49 mg, 0.15 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (44 mg, 0.15 mmol) using theprocedure in Example 115C to give1-(3-tert-butyl-1-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(15 mg, 0.028 mmol, 19%). ¹H NMR (300 MHz, MeOD) δ 8.76 (s, 1H), 8.55(s, 1H), 8.43 (s, 1H), 8.01 (s, 1H), 7.56-7.46 (m, 3H), 7.33-7.21 (m,3H), 6.92 (s, 1H), 6.40 (s, 1H), 3.99 (s, 6H), 1.32 (s, 9H); LC-MS (ESI)m/z 540 (M+H)⁺.

Example 323 Preparation of1-(3-tert-butyl-1-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

1-(3-tert-Butyl-1-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)ureawas obtained following the procedure described in Example 274B forsynthesis of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea,substituting phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate withphenyl 3-tert-butyl-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate in Example322A, and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline with3-(6,7-dimethoxyquinazolin-4-ylthio)aniline in Example 115 (0.018 g,8%). ¹H NMR (300 MHz, DMSO-d₆) δ 1.28 (s, 9H), 3.99 (s, 6H), 6.40 (s,1H), 7.24 (d, 1H), 7.33 (s, 1H), 7.35 (s, 1H), 7.40 (t, 1H), 7.45 (d,1H), 7.57 (dd, 1H), 7.78 (s, 1H), 7.97 (dd, 1H), 8.59 (d, 2H), 8.69 (s,1H), 8.78 (s, 1H), 9.24 (s, 1H); LC-MS (ESI) m/z 556 (M+H)⁺.

Example 324 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea

Example 324A Step 1: Using the procedure described in Example 308A Step1, to a solution of 4-methyl-3-oxopentanenitrile (303 mg, 2.7 mmol)prepared as described in Example 122A Step 1, in anhydrous EtOH (6 ml)was added phenylhydrazine hydrochloride (473 mg, 3.3 mmol) and thereaction mixture was heated at 65° C. overnight. The residue waspurified by silica gel chromatography (hexane/ethyl acetate 2-50%) toafford 3-isopropyl-1-phenyl-1H-pyrazol-5-amine (423 mg, 77%) as a solid.¹H NMR (300 MHz, CDCl₃) δ 1.22 (d, J=6 Hz, 6H), 3.86 (brs, 2H), 5.35 (s,1H), 7.21-7.49 (m, 5H); LC-MS (ESI) m/z 202 (M+H)⁺.

Example 324A Step 2: Using the procedure described in Example 306A, to asolution of 3-isopropyl-1-phenyl-1H-pyrazol-5-amine (423 mg, 2.1 mmol)and potassium carbonate (378 mg, 2.7 mmol) in anhydrous DCM (8 ml) wasadded dropwise phenyl chloroformate (0.39 ml, 3.1 mmol) as a solution inDCM (2 ml) to afford phenyl3-isopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate (229 mg, 54%). ¹H NMR (300MHz, CDCl₃) δ 1.27 (d, J=6 Hz, 6H), 3.01 (m, 1H), 6.46 (s, 1H),7.14-7.36 (m, 2H), 7.38-7.57 (m, 8H); LC-MS (ESI) m/z 322 (M+H)⁺.

Example 324B: Using the procedure described in Example 306B, to asolution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (92 mg, 0.31mmol), prepared as described in Example 113A, in THF (2 ml) was addedDMAP (20 mg, 0.16 mmol) and phenyl3-isopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate (100 mg, 0.31 mmol)described in the previous step. The suspension was triturated withanhydrous diethyl ether to afford1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea(98 mg, 60%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.21 (d, J=6.9 Hz,6H), 2.87 (m, 1H), 3.99 (s, 6H), 6.31 (s, 1H), 6.92 (d, J=7.8 Hz, 1H),7.18 (d, J=7.8 Hz, 1H), 7.34-7.40 (m, 3H), 7.52-7.55 (m, 6H), 8.47 (s,1H), 8.55 (s, 1H), 9.21 (s, 1H); LC-MS (ESI) m/z 525 (M+H)⁺.

Example 325 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea

Using the procedure described in Example 306A, to a solution of3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (125 mg, 0.4 mmol), preparedas described in Example 115B, in THF (2 ml) was added DMAP (20 mg, 0.16mmol) and phenyl 3-isopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate (129 mg,0.4 mmol) described in Example 324A. The suspension was filtered andtriturated with anhydrous diethyl ether to afford1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea(154 mg, 71%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.22 (d, J=7.2 Hz,6H), 2.88 (m, 1H), 3.99 (s, 6H), 6.32 (s, 1H), 7.24 (d, J=7.5 Hz, 1H),7.25-7.53 (m, 10H), 7.79 (m, 1H), 8.47 (s, 1H), 8.69 (s, 1H), 9.21 (s,1H); LC-MS (ESI) m/z 541 (M+H)⁺.

Example 326 Preparation of1-(3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 326A Step 1: To a stirred and degassed solution of3-bromo-5-fluoropyridine (1 g, 5.68 mmol), benzophenone hydrazone (1.23g, 6.25 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (329mg, 0.57 mmol) in anhydrous toluene (15 mL) at rt under an argonatmosphere, was added palladium acetate (128 mg, 0.57 mmol). The vesselwas sealed and heated at 85° C. for 15 h. The reaction mixture wascooled to rt and partitioned between ethyl acetate and water. Theorganic layer was separated and washed with water, then brine, thendried over magnesium sulfate and filtered. Concentration under reducedpressure gave a brown solid which was purified via silica gel columnchromatography (eluting with a gradient of 12% ethyl acetate in hexanesto 100% ethyl acetate) to afford3-(2-(diphenylmethylene)hydrazinyl)-5-fluoropyridine (1.35 g, 82%) as ayellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.41 (s, 1H), 8.41 (s, 1H),7.95 (s, 1H), 7.30-7.65 (m, 11H); LC-MS (ESI) m/z 292 (M+H)⁺.

Example 326A Step 2: A stirred mixture of3-(2-(diphenylmethylene)hydrazinyl)-5-fluoropyridine (1.35 g, 4.64mmol), 4,4-dimethyl-3-oxopentanenitrile (871 mg, 6.96 mmol) andp-toluenebenzenesulfonic acid monohydrate (4.41 g, 23 mmol) in ethanol(18 mL) was heated at 90° C. for 15 h. After cooling to rt, the mixturewas concentrated under reduced pressure and the residue partitionedbetween ethyl acetate and saturated aqueous sodium hydrogen carbonatesolution. The organic layer was separated, washed with water, saturatedaqueous sodium hydrogen carbonate solution, then dried over magnesiumsulfate and filtered. Concentration under reduced pressure gave an oilwhich was purified via silica gel column chromatography (eluting with agradient of 12% ethyl acetate in hexanes to 100% ethyl acetate) toafford 3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-amine (384 mg,35%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.77 (s, 1H), 8.47 (s, 1H),7.92 (s, 1H), 5.51 (s, 1H), 5.46 (brs, 2H), 1.20 (s, 9H); LC-MS (ESI)m/z 235 (M+H)⁺.

Example 326A Step 3: Using the procedure described in Example 306A, to asolution of 3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-amine(423 mg, 2.1 mmol), described in the previous step, and potassiumcarbonate (290 mg, 2.1 mmol) in anhydrous DCM (3.4 ml) was addeddropwise phenyl chloroformate (0.61 ml, 4.8 mmol) as a solution in DCM(2 ml) to afford phenyl3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-ylcarbamate (411 mg,72%). ¹H NMR (300 MHz, CDCl₃) δ 1.28 (s, 9H), 6.47 (s, 1H), 6.95-7.41(m, 7H), 7.72-7.82 (m, 1H), 8.40 (d, J=8 Hz, 1H); LC-MS (ESI) m/z 355(M+H)⁺.

Example 326B: Using the procedure described in Example 306A, to asolution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3mmol), prepared as described in Example 113A, in THF (3.3 ml) was addedDMAP (20 mg, 0.16 mmol) and phenyl3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-ylcarbamate (159 mg,0.45 mmol), described in the previous step, to afford1-(3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(84 mg, 50%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.27 (s, 9H),3.97-3.99 (m, 6H), 6.42 (s, 1H), 6.93 (d, J=7.8 Hz, 1H), 7.20 (d, J=8.1Hz, 1H), 7.34-7.40 (m, 2H), 7.54 (d, J=5.1 Hz, 2H), 7.98 (d, J=10 Hz,1H), 8.55 (s, 1H), 8.61-8.71 (m, 3H), 9.24 (s, 1H); LC-MS (ESI) m/z 558(M+H)⁺.

Example 327 Preparation of1-(3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

Using the procedure described in Example 306A, to a solution of3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), preparedas described in Example 115B, in THF (3.3 ml) was added DMAP (20 mg,0.16 mmol) and phenyl3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-ylcarbamate (159 mg,0.45 mmol) described in Example 326A to afford1-(3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(107 mg, 62%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.28 (s, 9H), 3.99(m, 6H), 6.43 (s, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.34 (d, J=4.5 Hz, 2H),7.38-7.47 (m, 2H), 7.54 (s, 1H), 7.98 (d, J=9.9 Hz, 1H), 8.61-8.72 (m,4H), 9.25 (s, 1H); LC-MS (ESI) m/z 574 (M+H)⁺.

Example 328 Preparation of1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 328A Step 1: Using the procedure described in Example 308A Step1, to a solution of 4,4-dimethyl-3-oxopentanenitrile (1 g, 7.99 mmol) inanhydrous EtOH (55 ml) was added 4-cyanophenyl hydrazine hydrochloride(473 mg, 3.3 mmol) and the reaction mixture was heated at 80° C.overnight. The residue was purified by silica gel chromatography(DCM/EtOAc 40%) to afford4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)benzonitrile (350 mg, 18%) as asolid. ¹H NMR (300 MHz, CDCl₃) δ 1.3 (s, 9H), 3.75 (brs, 2H), 7.72 (d,J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz, 2H); LC-MS (ESI) m/z 241 (M+H)⁺.

Example 328A Step 2: Using the procedure described in Example 306A, to asolution of 4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)benzonitrile (350mg, 1.45 mmol) and potassium carbonate (263 mg, 1.9 mmol) in anhydrousDCM (3 ml) was added dropwise phenyl chloroformate (0.91 ml, 7.3 mmol)as a solution in DCM (1.5 ml). The crude was purified by silica gelchromatography (DCM/EtOAc 6-50%) to afford phenyl3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-ylcarbamate (320 mg, 61%).¹H NMR (300 MHz, CDCl₃) δ 1.34 (s, 9H), 6.45 (s, 1H), 7.26-7.28 (m, 3H),7.31-7.38 (m, 2H), 7.75-7.82 (m, 4H); LC-MS (ESI) m/z 362 (M+H)⁺.

Example 328B: Using the procedure described in Example 306A, to asolution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3mmol), prepared as described in Example 113A, in THF (3.3 ml) was addedDMAP (20 mg, 0.16 mmol) and phenyl3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-ylcarbamate (108 mg, 0.3mmol), described in the previous step, to afford1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(60 mg, 60%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.21 (s, 9H), 3.99(s, 6H), 6.40 (s, 1H), 6.93 (d, J=7.8 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H),7.34-7.40 (m, 2H), 7.52-7.55 (m, 2H), 7.79 (d, J=7.8 Hz, 2H), 7.99 (d,J=7.8 Hz, 2H), 8.55 (s, 1H), 8.62 (s, 1H), 9.24 (s, 1H); LC-MS (ESI) m/z564 (M+H)⁺.

Example 329 Preparation of1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

Using the procedure described in Example 306A, to a solution of3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), preparedas described in Example 115B, in THF (3.3 ml) was added DMAP (20 mg,0.16 mmol) and phenyl3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-ylcarbamate (108 mg, 0.3mmol) described in Example 328A, to afford1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(8 mg, 4%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.28 (s, 9H), 3.99(m, 6H), 6.41 (s, 1H), 7.24-7.41 (m, 6H), 7.79 (d, J=8.7 Hz, 2H), 7.98(d, J=8.7 Hz, 2H), 8.62 (s, 1H), 8.69 (s, 1H), 9.25 (s, 1H); LC-MS (ESI)m/z 580 (M+H)⁺.

Example 330 Preparation of1-(3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 330A Step 1: A stirred solution of cyclohexylhydrazinehydrochloride (1.5 g, 9.96 mmol) and 4,4-dimethyl-3-oxopentanenitrile(1.5 g, 11.98 mmol) in ethanol (5 mL) was refluxed for 15 h. Aftercooling to rt, the reaction mixture was concentrated under reducedpressure and the obtained crude product was recrystallized from amixture of diethyl ether and petroleum ether to afford3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-amine hydrochloride (1.0 g, 39%)as colorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.24 (brs, 1H), 7.02(brs, 2H), 5.52 (s, 1H), 4.30 (m, 1H), 1.63-1.98 (m, 7H), 1.10-1.40 (m,12H); LC-MS (ESI) m/z 222 (M+H)⁺.

Example 330A Step 2: To a stirred mixture of3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-amine hydrochloride (260 mg, 1mmol) and potassium carbonate (210 mg, 1.5 mmol) in THF (3 mL) at rt,was added dropwise a solution of phenyl chloroformate (170 mg, 1.1 mmol)in THF (2 mL) and the reaction mixture was stirred for a further 15 h.N,N-Diisopropylethylamine (129 mg, 1 mmol) was added to the reactionmixture and stirring continued for an additional 4 h. The reactionmixture was filtrated, the filtrate concentrated under reduced pressureand the residue partitioned between dichloromethane and water. Theorganic layer was separated and washed with brine, then concentratedunder reduced pressure to give a solid which was recrystallized fromdiethyl ether to afford crude phenyl3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-ylcarbamate (200 mg) which wasused without further purification. LC-MS (ESI) m/z 342 (M+H)⁺.

Example 330B: A stirred solution of phenyl3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-ylcarbamate (200 mg),N,N-Diisopropylethylamine (67 mg, 0.52 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described inExample 113A) (80 mg, 0.26 mmol) in THF (1.0 mL) was heated at 60° C.for 15 h. After cooling to rt, the reaction solution was partitionedbetween dichloromethane and a saturated aqueous solution of sodiumcarbonate. The organic phase was separated and concentrated underreduced pressure. The crude product was purified via silica gel columnchromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane:methanol) then reverse-phase preparative HPLC to afford1-(3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(55 mg, 10% over two steps) as a pale yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.10 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 7.57-7.60 (m, 2H),7.37-7.41 (m, 2H), 7.24 (m, 1H), 6.93 (m, 1H), 6.01 (s, 1H), 4.00 (s,3H), 3.99 (s, 3H), 3.94 (m, 1H), 1.62-1.82 (m, 8H), 1.24-1.35 (m, 2H),1.24 (s, 9H); LC-MS (ESI) m/z 545 (M+H)⁺.

Example 331 Preparation of1-(3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

A stirred solution of phenyl3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-ylcarbamate prepared as describedin Example 330A (200 mg, 0.59 mmol), N,N-diisopropylethylamine (67 mg,0.52 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared asdescribed in Example 115B) (85 mg, 0.27 mmol) in THF (1.0 mL) was heatedat 60° C. for 15 h. After cooling to rt, the reaction solution waspartitioned between dichloromethane and a saturated aqueous solution ofsodium carbonate. The organic phase was separated and concentrated underreduced pressure. The crude product was purified via silica gel columnchromatography (eluting with a gradient of 40:1 to 20:1dichloromethane:methanol) then reverse-phase preparative HPLC to afford1-(3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(52 mg, 18%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.17(s, 1H), 8.71 (s, 1H), 8.53 (s, 1H), 7.84 (s, 1H), 7.26-7.55 (m, 5H),6.06 (s, 1H), 4.00 (s, 6H), 3.94 (m, 1H), 1.62-1.81 (m, 7H), 1.24-1.36(m, 12H); LC-MS (ESI) m/z 561 (M+H)⁺.

Example 332 Preparation of1-(3-tert-butyl-1-isobutyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 332A Step 1: A stirred solution of isobutylhydrazinehydrochloride (1 g, 8 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.2 g,9.6 mmol) in ethanol (5 mL) was refluxed for 15 h. After cooling to rt,the reaction mixture was concentrated under reduced pressure and theobtained crude product was recrystallized from a mixture of diethylether and petroleum ether to afford3-tert-butyl-1-isobutyl-1H-pyrazol-5-amine hydrochloride (0.8 g, 43%) ascolorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ 14.06 (brs, 1H), 6.93 (brs,2H), 5.52 (s, 1H), 3.92 (m, 2H), 2.16 (m, 1H), 1.26 (s, 9H), 0.83 (m,6H); LC-MS (ESI) m/z 196 (M+H)⁺.

Example 332A Step 2: Following the procedure described for Example 330AStep 2, reaction of 3-tert-butyl-1-isobutyl-1H-pyrazol-5-aminehydrochloride with phenyl chloroformate, afforded phenyl3-tert-butyl-1-isobutyl-1H-pyrazol-5-ylcarbamate which was used in thesubsequent step.

Example 332B: A stirred solution of phenyl3-tert-butyl-1-isobutyl-1H-pyrazol-5-ylcarbamate (150 mg, 0.47 mmol),N,N-Diisopropylethylamine (80 mg, 0.62 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described inExample 113A) (92 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60° C.for 15 h. After cooling to rt, the reaction solution was partitionedbetween dichloromethane and a saturated aqueous solution of sodiumcarbonate. The organic phase was separated and concentrated underreduced pressure. The crude product was purified via silica gel columnchromatography (eluting with a gradient of 40:1 to 20:1dichloromethane:methanol) then reverse-phase preparative HPLC to afford1-(3-tert-butyl-1-isobutyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(60 mg, 38%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.09(s, 1H), 8.57 (s, 1H), 8.49 (s, 1H), 7.61 (m, 1H), 7.57 (m, 1H),7.37-7.41 (m, 2H), 7.24 (m, 1H), 6.94 (m, 1H), 6.01 (s, 1H), 4.00 (s,3H), 3.99 (s, 3H), 3.71 (d, J=7.6 Hz, 2H), 2.07 (m, 1H), 1.20 (s, 9H),0.83 (d, J=6.4 Hz, 6H); LC-MS (ESI) m/z 519 (M+H)⁺.

Example 333 Preparation of1-(3-tert-butyl-1-isobutyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

A stirred solution of phenyl3-tert-butyl-1-isobutyl-1H-pyrazol-5-ylcarbamate described in Example332A (150 mg, 0.47 mmol), N,N-diisopropylethylamine (80 mg, 0.62 mmol)and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as describedin Example 115B) (100 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60°C. for 15 h. After cooling to rt, the reaction solution was partitionedbetween dichloromethane and a saturated aqueous solution of sodiumcarbonate. The organic phase was separated and concentrated underreduced pressure. The crude product was purified via silica gel columnchromatography (eluting with a gradient of 40:1 to 20:1dichloromethane:methanol) then reverse-phase preparative HPLC to afford1-(3-tert-butyl-1-isobutyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(52 mg, 32%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.07(s, 1H), 8.70 (s, 1H), 8.48 (s, 1H), 7.85 (s, 1H), 7.24-7.53 (m, 5H),6.07 (s, 1H), 4.00 (s, 6H), 3.72 (d, J=7.2 Hz, 2H), 2.07 (m, 1H), 1.20(s, 9H), 0.83 (d, J=6.8 Hz, 6H); LC-MS (ESI) m/z 535 (M+H)⁺.

Example 334 Preparation of1-(3-tert-butyl-1-isopropyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 334A Step 1: A stirred solution of isopropylhydrazinehydrochloride (500 mg, 4.54 mmol) and 4,4-dimethyl-3-oxopentanenitrile(679 mg, 5.44 mmol) in ethanol (5 mL) was refluxed for 15 h. Aftercooling to rt, the reaction mixture was concentrated under reducedpressure and the obtained crude product was recrystallized from amixture of diethyl ether and petroleum ether to afford3-tert-butyl-1-isopropyl-1H-pyrazol-5-amine hydrochloride (500 mg, 51%)as colorless solid. ¹H NMR (400 MHz, CDCl₃) δ 5.55 (s, 1H), 5.05 (brs,2H), 3.62 (m, 1H), 1.68 (d, J=6.4 Hz, 6H), 1.43 (s, 9H); LC-MS (ESI) m/z182 (M+H)⁺.

Example 334A Step 2: To a mixture of phenyl chloroformate (170 mg, 1.1mmol) and potassium carbonate (210 mg, 1.5 mmol) in DCM (3 mL) at 0° C.,was added dropwise a solution of3-tert-butyl-1-isopropyl-1H-pyrazol-5-amine hydrochloride (220 mg, 1mmol) in N,N-diisopropylethylamine (130 mg, 1 mmol) and the reactionmixture was stirred at 0° C. for 3 h. The mixture was filtrated,concentrated under reduced pressure, and the residue dissolved indichloromethane. The organic phase was washed water, brine andconcentrated under reduced pressure to give the crude product which waspurified via recrystallization from diethyl ether to afford phenyl3-tert-butyl-1-isopropyl-1H-pyrazol-5-ylcarbamate (300 mg, 100%) as acolorless solid. LC-MS (ESI) m/z 302 (M+H)⁺.

Example 334B: A stirred solution of phenyl3-tert-butyl-1-isopropyl-1H-pyrazol-5-ylcarbamate (150 mg, 0.50 mmol),N,N-Diisopropylethylamine (80 mg, 0.62 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described inExample 113A) (92 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60° C.for 15 h. After cooling to rt, the reaction solution was partitionedbetween dichloromethane and a saturated aqueous solution of sodiumcarbonate. The organic phase was separated and concentrated underreduced pressure. The crude product was purified via silica gel columnchromatography (eluting with a gradient of 40:1 to 20:1dichloromethane:methanol) then reverse-phase preparative HPLC to afford1-(3-tert-butyl-1-isopropyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(62 mg, 40%) as a colorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (s,1H), 8.57 (s, 1H), 8.43 (s, 1H), 7.55-7.59 (m, 2H), 7.37-7.40 (m, 2H),7.24 (m, 1H), 6.93 (m, 1H), 6.00 (s, 1H), 4.35 (m, 1H), 4.00 (s, 3H),3.99 (s, 3H), 1.34 (d, J=6.4 Hz, 6H), 1.24 (s, 9H); LC-MS (ESI) m/z 505(M+H)⁺.

Example 335 Preparation of1-(3-tert-butyl-1-isopropyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

A stirred solution of phenyl3-tert-butyl-1-isopropyl-1H-pyrazol-5-ylcarbamate described in Example334A (150 mg, 0.50 mmol), N,N-Diisopropylethylamine (80 mg, 0.62 mmol)and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described inExample 113A) (100 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60° C.for 15 h. After cooling to rt, the reaction solution was partitionedbetween dichloromethane and a saturated aqueous solution of sodiumcarbonate. The organic phase was separated and concentrated underreduced pressure. The crude product was purified via silica gel columnchromatography (eluting with a gradient of 40:1 to 20:1dichloromethane:methanol) then reverse-phase preparative HPLC to afford1-(3-tert-butyl-1-isopropyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(60 mg, 37%) as a colorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.26 (s,1H), 8.71 (s, 1H), 8.60 (s, 1H), 7.83 (m, 1H), 7.53 (m, 1H), 7.43 (m,1H), 7.35-7.36 (m, 2H), 7.25 (m, 1H), 6.02 (s, 1H), 4.32 (m, 1H), 4.00(s, 6H), 1.34 (d, J=6.4 Hz, 6H), 1.21 (s, 9H); LC-MS (ESI) m/z 521(M+H)⁺.

Example 336 Preparation of1-(3-tert-butyl-1-(pyridin-4-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 336A Step 1: Following the procedure in Example 161A Step3,4-hydrazinopyridine hydrochloride (1.0 g, 6.87 mmol) and4,4-dimethyl-3-oxopentanenitrile (860 mg, 6.87 mmol) were reacted togive 3-tert-butyl-1-(pyridin-4-yl)-1H-pyrazol-5-amine (250 mg, 1.16mmol, 17%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.55 (br s, 2H), 7.69 (br s,2H), 5.55 (br s, 2H), 5.46 (s, 1H), 1.22 (s, 9H); LC-MS (ESI) m/z 217(M+H)⁺.

Example 336A Step 2: Following the procedure in Example 118A,3-tert-butyl-1-(pyridin-4-yl)-1H-pyrazol-5-amine (250 mg, 1.16 mmol) andphenyl chloroformate (0.60 mL, 4.65 mmol) were reacted to give phenyl3-tert-butyl-1-(pyridin-4-yl)-1H-pyrazol-5-ylcarbamate (90 mg, 0.27mmol, 23%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.15 (br s, 1H), 8.72 (d, 2H),7.76 (d, 2H), 7.40-7.05 (m, 5H), 6.45 (s, 1H), 1.29 (s, 9H); LC-MS (ESI)m/z 337 (M+H)⁺.

Example 336B: The title compound was prepared from the carbamate fromthe previous step (45 mg, 0.13 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (40 mg, 0.13 mmol) using theprocedure in Example 115C to give1-(3-tert-butyl-1-(pyridin-4-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(22 mg, 0.041 mmol, 31%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H),8.72-8.64 (m, 3H), 8.56 (s, 1H), 7.68-7.62 (m, 2H), 7.51 (br s, 2H),7.41-7.33 (m, 2H), 7.24 (d, 1H), 6.95 (d, 1H), 6.41 (s, 1H), 3.99 (s,6H), 1.29 (s, 9H); LC-MS (ESI) m/z 540 (M+H)⁺.

Example 337 Preparation of1-(3-tert-butyl-1-(pyridin-4-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared from the carbarbamate from Example 336A(45 mg, 0.13 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (42mg, 0.13 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-(pyridin-4-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(13 mg, 0.023 mmol, 18%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H),8.70-8.61 (m, 4H), 7.81 (s, 1H), 7.68-7.65 (m, 2H), 7.51 (d, 1H), 7.42(t, 1H), 7.35-7.33 (m, 2H), 7.25 (d, 1H), 6.42 (s, 1H), 3.99 (s, 6H),1.30 (s, 9H); LC-MS (ESI) m/z 556 (M+H)⁺.

Example 338 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

Example 338A Step 1: Following the procedure in Example 161A Step 3,m-tolylhydrazine hydrochloride (1.15 g, 7.30 mmol) and4,4,4-trifluoro-3-oxobutanenitrile (1.0 g, 7.30 mmol) were reacted togive 1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (380 mg, 1.57mmol, 22%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.60-7.20 (m, 4H), 5.82-5.61 (m,3H), 2.59 (s, 3H); LC-MS (ESI) m/z 242 (M+H)⁺.

Example 338A Step 2: Following the procedure in Example 118A,1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (380 mg, 1.58 mmol) andphenyl chloroformate (0.60 mL, 4.74 mmol) were reacted to give phenyl1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate (330 mg, 0.91mmol, 58%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.4 (br s, 1H), 7.62-6.85 (m,10H), 2.46 (s, 3H); LC-MS (ESI) m/z 362 (M+H)⁺.

Example 338B: The title compound was prepared from the carbamate fromthe previous step (108 mg, 0.30 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (90 mg, 0.30 mmol) using theprocedure in Example 115C to give1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea(140 mg, 0.25 mmol, 83%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 8.77(s, 1H), 8.55 (s, 1H), 7.55-7.36 (m, 8H), 7.21 (d, 1H), 6.95 (d, 1H),6.85 (s, 1H), 3.97 (s, 6H), 2.41 (s, 3H); LC-MS (ESI) m/z 565 (M+H)⁺.

Example 339 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

The title compound was prepared from the carbamate from Example 338A(108 mg, 0.30 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94mg, 0.30 mmol) using the procedure in Example 115C to give1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea(137 mg, 0.24 mmol, 79%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.31 (s, 1H), 8.76(s, 1H), 8.68 (s, 1H), 7.78 (s, 1H), 7.52-7.25 (m, 9H), 6.86 (s, 1H),3.98 (s, 6H), 2.41 (s, 3H); LC-MS (ESI) m/z 581 (M+H)⁺.

Example 340 Preparation of1-(3-tert-butyl-1-(2-chlorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 340A Step 1: Following the procedure in Example 161A Step3,2-chlorophenylhydrazine hydrochloride (1.43 g, 8.0 mmol) and4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) were reacted to give3-tert-butyl-1-(2-chlorophenyl)-1H-pyrazol-5-amine (1.30 g, 5.22 mmol,65%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.60 (d, 1H), 7.48-7.42 (m, 3H), 5.28(s, 1H), 4.94 (s, 2H), 1.19 (s, 9H); LC-MS (ESI) m/z 250 (M+H)⁺.

Example 340A Step 2: Following the procedure in Example 118A,3-tert-butyl-1-(2-chlorophenyl)-1H-pyrazol-5-amine (1.30 g, 5.21 mmol)and phenyl chloroformate (2.0 mL, 15.63 mmol) were reacted to givephenyl 3-tert-butyl-1-(2-chlorophenyl)-1H-pyrazol-5-ylcarbamate. ¹H NMR(300 MHz, DMSO-d₆) δ 10.18 (br s, 1H), 7.67 (d, 1H), 7.55-7.48 (m, 3H),7.41-7.36 (m, 2H), 7.24 (t, 1H), 7.02 (br s, 2H), 6.31 (s, 1H), 1.23 (s,9H); LC-MS (ESI) m/z 370 (M+H)⁺.

Example 340B: The title compound was prepared from the carbamate fromthe previous step (111 mg, 0.30 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (90 mg, 0.30 mmol) using theprocedure in Example 115C to give1-(3-tert-butyl-1-(2-chlorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(92 mg, 0.16 mmol, 53%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.06 (s, 1H), 8.55(s, 1H), 8.35 (s, 1H), 7.73 (d, 1H), 7.57-7.54 (m, 5H), 7.38-7.34 (m,2H), 7.13 (d, 1H), 6.93 (d, 1H), 6.35 (s, 1H), 3.99 (s, 6H), 1.25 (s,9H); LC-MS (ESI) m/z 573 (M)⁺.

Example 341 Preparation of1-(3-tert-butyl-1-(2-chlorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared from the carbamate in Example 340A (111mg, 0.30 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg,0.30 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-(2-chlorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(120 mg, 0.20 mmol, 68%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.06 (s, 1H), 8.68(s, 1H), 8.34 (s, 1H), 7.80 (s, 1H), 7.72 (d, 1H), 7.60-7.54 (m, 3H),7.41-7.32 (m, 4H), 7.25 (d, 1H), 6.35 (s, 1H), 3.98 (s, 6H), 1.25 (s,9H); LC-MS (ESI) m/z 589 (M+H)⁺.

Example 342 Preparation of1-(3-tert-butyl-1-o-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 342A Step 1: Following the procedure for Example 282A Step 1,substituting 2,4-dimethylphenylhydrazine hydrochloride foro-tolylhydrazine afforded 3-tert-butyl-1-o-tolyl-1H-pyrazol-5-amine (973mg, 53% yield). LC-MS (ESI) m/z 230 (M+H)⁺

Example 342A Step 2: Following the procedure for Example 282A Step 2,using 3-tert-butyl-1-o-tolyl-1H-pyrazol-5-amine from step A affordedphenyl 3-tert-butyl-1-o-tolyl-1H-pyrazol-5-ylcarbamate (730 mg, 49%yield). LC-MS (ESI) m/z 350 (M+H)⁺

Example 342B: The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol) and thecarbamate from the previous step (115 mg, 0.33 mmol) using procedure inExample 115C to give1-(3-tert-butyl-1-o-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(111 mg, 0.20 mmol, 67%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.13 (s, 1H), 8.55(s, 1H), 8.23 (s, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 7.46-7.33 (m, 6H),7.12 (d, 1H), 6.93 (d, 1H), 6.34 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H),2.00 (s, 3H), 1.26 (s, 9H); LC-MS (ESI) m/z 553 (M+H)⁺.

Example 343 Preparation of1-(3-tert-butyl-1-o-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol) and thecarbamate from Example 343A (115 mg, 0.33 mmol) using the procedure inExample 115C to give1-(3-tert-butyl-1-o-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(118 mg, 0.21 mmol, 77%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.13 (s, 1H), 8.68(s, 1H), 8.23 (s, 1H), 7.79 (s, 1H), 7.43-7.32 (m, 8H), 7.23 (d, 1H),6.35 (s, 1H), 3.99 (s, 6H), 2.01 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z569 (M+H)⁺.

Example 344 Preparation of1-(3-tert-Butyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 344A Step 1: 3-tert-Butyl-1-(pyridin-2-yl)-1H-pyrazol-5-aminewas obtained following the procedure described in Example 274A Step 1for synthesis of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine, substitutingp-tolylhydrazine hydrochloride with 2-hydrazinylpyridine dihydrochloride(1.874 g, 85% yield). LC-MS (ESI) m/z 217 (M+H)⁺.

Example 344A Step 2: Phenyl3-tert-butyl-1-(pyridin-2-yl)-1H-pyrazol-5-ylcarbamate was obtainedfollowing the procedure described in Example 274A Step 2 for synthesisof phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate, substituting3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine with3-tert-butyl-1-(pyridin-2-yl)-1H-pyrazol-5-amine (2.845 g, 99%). ¹H NMR(300 MHz, CDCl₃) δ 1.34 (s, 9H), 6.62 (s, 1H), 7.24 (m, 4H), 7.42 (t,2H), 7.83 (t, 1H), 8.09 (d, 1H), 8.36 (d, 1H), 11.84 (s, 1H); LC-MS(ESI) m/z 337 (M+H)⁺.

Example 344B:1-(3-tert-Butyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)ureawas obtained following the procedure described in Example 274B forsynthesis of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea,substituting phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate withphenyl 3-tert-butyl-1-(pyridin-2-yl)-1H-pyrazol-5-ylcarbamate (0.127 g,59%). ¹H NMR (300 MHz, DMSO-d₆) δ 1.28 (s, 9H), 3.99 (s, 3H), 4.00 (s,3H), 6.59 (s, 1H), 6.98 (d, 1H), 7.32 (m, 2H), 7.40 (m, 2H), 7.57 (s,1H), 7.66 (s, 1H), 7.91 (d, 1H), 8.01 (t, 1H), 8.48 (d, 1H), 8.57 (s,1H), 10.13 (s, 1H), 11.27 (s, 1H); LC-MS (ESI) m/z 540 (M+H)⁺.

Example 345 Preparation of1-(3-tert-butyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

1-(3-tert-Butyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)ureawas obtained following the procedure described in Example 274B forsynthesis of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea,substituting phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate withphenyl 3-tert-butyl-1-(pyridin-2-yl)-1H-pyrazol-5-ylcarbamate in Example344A, and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline with3-(6,7-dimethoxyquinazolin-4-ylthio)aniline in Example 115 (0.017 g,7.7%). ¹H NMR (300 MHz, DMSO-d₆) δ 1.29 (s, 9H), 4.00 (s, 6H), 6.60 (s,1H), 7.27-7.36 (m, 4H), 7.46 (t, 1H), 7.63 (d, 1H), 7.91 (d, 2H), 8.02(dt, 1H), 8.47 (d, 1H), 8.71 (s, 1H), 10.12 (s, 1H), 11.28 (s, 1H);LC-MS (ESI) m/z 556 (M+H)⁺.

Example 346 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea

Example 346A Step 1: To a solution of3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile (500 mg, 2.8mmol) (from Example 137A Step 2) in EtOH (10 mL) was added water (7.2mL) and 1 M NaOH (2.8 mL) followed by p-tolylhydrazine hydrochloride(444 mg, 2.8 mmol) and the solution heated at 80° C. overnight. Thesolution was cooled to rt, diluted with water and extracted with 2portions of EtOAc. The combined extracts were washed with brine, driedover magnesium sulfate, filtered, and concentrated. The crude solid waspurified using silica gel chromatography using a gradient of 5-25%EtOAc/hexane to give1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (452 mg,57% yield). LC-MS (ESI) m/z 282 (M+H)⁺

Example 346A Step 2: To a solution of1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (574 mg,2.0 mmol) in DCM (20 mL) was added K₂CO₃ (423 mg, 3.06 mmol) and phenylchloroformate (386 μL, 3.06 mmol). The solution was stirred at rtovernight. The reaction mixture was filtered and the solids washed withDCM, the filtrate concentrated and purified using silica gelchromatography eluting with an EtOAC/Hexane gradient (5-20%) to givephenyl1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-ylcarbamate(1.04 g, quantitative yield). ¹H NMR (300 MHz, DMSO d₆) δ 1.33 (m, 4H),2.34 (s, 3H), 6.51 (s, 1H), 7.12 (m, 2H), 7.23 (m, 1H), 7.37 (m, 6H),10.13 (s, 1H); LC-MS (ESI) m/z 402 (M+H)⁺

Example 346B: The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol) and thecarbamate from the previous step (120 mg, 0.3 mmol) using the procedurein Example 115C to give1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea(170 mg, 0.28 mmol, 94%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H), 8.55(br s, 2H), 7.56 (br s, 2H), 7.54-7.32 (m, 6H), 7.17 (d, 1H), 6.94 (d,1H), 6.54 (s, 1H), 3.99 (s, 6H), 2.38 (s, 3H), 1.40-1.25 (m, 4H); LC-MS(ESI) m/z 605 (M+H)⁺.

Example 347 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea

The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol) and thecarbamate from Example 346A (120 mg, 0.3 mmol) using the procedure inExample 115C to give1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea(152 mg, 0.25 mmol, 82%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 8.69(s, 1H), 8.55 (s, 1H), 7.79 (s, 1H), 7.51-7.32 (m, 8H), 7.25 (d, 1H),6.54 (s, 1H), 3.99 (s, 6H), 2.38 (s, 3H), 1.38-1.27 (m, 4H); LC-MS (ESI)m/z 621 (M+H)⁺.

Example 348 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)urea

Example 348A Step 1: Using the procedure described in Example 308A Step1, to a solution of 4-methyl-3-oxopentanenitrile (514 mg, 4.5 mmol)prepared as described in Example 122A Step 1, in anhydrous EtOH (15 ml)was added (4-methoxyphenyl)hydrazine hydrochloride (524 mg, 3.0 mmol)and the reaction mixture was heated at 80° C. overnight. The residue waspurified by silica gel chromatography (DCM/EtOAc 1:1) to afford3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (333 mg, 48%) as asolid. ¹H NMR (300 MHz, CDCl₃) δ 1.26 (d, J=7 Hz, 6H), 2.92 (m, 1H),3.66 (s, 2H), 3.83 (s, 3H), 5.46 (s, 1H), 6.96 (d, J=9 Hz, 2H), 7.44 (d,J=9 Hz, 2H); LC-MS (ESI) m/z 232 (M+H)⁺.

Example 348A Step 2: Using the procedure described in Example 306A, to asolution of 3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (333 mg,1.45 mmol) and potassium carbonate (261 mg, 1.89 mmol) in anhydrous DCM(5.3 ml) was added dropwise phenyl chloroformate (0.55 ml, 4.34 mmol) asa solution in DCM (3.5 ml). The crude was purified by silica gelchromatography (DCM/MeOH 0-10%) to afford phenyl3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-ylcarbamate (500 mg, 98%).¹H NMR (300 MHz, CDCl₃) δ 1.30 (d, J=7 Hz, 6H), 2.99 (m, 1H), 3.87 (s,3H), 6.41 (s, 1H), 7.03 (d, J=9 Hz, 2H), 7.11-7.14 (m, 2H), 7.23-7.26(m, 2H), 7.35-7.42 (m, 4H); LC-MS (ESI) m/z 352 (M+H)⁺.

Example 348B: Using the procedure described in Example 306A, to asolution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3mmol), prepared as described in Example 113A, in THF (3.3 ml) was addedDMAP (20 mg, 0.16 mmol) and phenyl3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-ylcarbamate (105 mg, 0.3mmol), described in the previous step, to afford1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)urea(65 mg, 39%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.20 (d, J=7 Hz,6H), 2.85 (m, 1H), 3.81 (s, 3H), 3.97 (s, 6H), 6.27 (s, 1H), 6.91 (d,J=7.5 Hz, 1H), 7.07 (d, J=9 Hz, 2H), 7.16 (d, J=9 Hz, 1H), 7.33-7.41 (m,4H), 7.55 (s, 2H), 8.35 (s, 1H), 8.55 (s, 1H), 9.18 (s, 1H); LC-MS (ESI)m/z 555 (M+H)⁺.

Example 349 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)urea

Using the procedure described in Example 306A, to a solution of3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), preparedas described in Example 115B, in THF (3.3 ml) was added DMAP (23 mg,0.18 mmol) and phenyl3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-ylcarbamate (105 mg, 0.3mmol), described in Example 348A, to afford1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)urea(101 mg, 59%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.21 (d, J=7 Hz,6H), 2.86 (s, 1H), 3.81 (s, 3H), 3.99 (s, 6H), 6.28 (s, 1H), 7.07 (d,J=8.7 Hz, 2H), 7.23 (d, J=7.5 Hz, 1H), 7.34 (d, J=5 Hz, 2H), 7.39-7.44(m, 4H), 7.79 (s, 1H), 8.35 (s, 1H), 8.68 (s, 1H), 9.18 (s, 1H); LC-MS(ESI) m/z 571 (M+H)⁺.

Example 350 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-yl)urea

Example 350A Step 1: Using the procedure described in Example 308A Step1, to a solution of 4-methyl-3-oxopentanenitrile (303 mg, 2.7 mmol)prepared as described in Example 122A Step 1, in anhydrous EtOH (13 ml)was added 3-hydrazinylpyridine hydrochloride (450 mg, 3.1 mmol) and thereaction mixture was heated at 80° C. overnight to afford3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-amine (179 mg, 28%) as asolid. ¹H NMR (300 MHz, CDCl₃) δ 1.25 (d, J=7 Hz, 6H), 2.90-2.99 (m,1H), 3.93 (brs, 2H), 5.50 (s, 1H), 7.36-7.38 (m, 1H), 7.96 (d, J=8 Hz,1H), 8.49 (d, J=7 Hz, 1H), 8.67 (s, 1H); LC-MS (ESI) m/z 203 (M+H)⁺.

Example 350A Step 2: Using the procedure described in Example 306A, to asolution of 3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-amine (179 mg,0.89 mmol) and potassium carbonate (159 mg, 1.2 mmol) in anhydrous DCM(3 ml) was added dropwise phenyl chloroformate (0.33 ml, 2.6 mmol) as asolution in DCM (0.2 ml). The crude was purified by silica gelchromatography (DCM/MeOH 0-10%) to afford phenyl3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate (217 mg, 76%). ¹HNMR (300 MHz, CDCl₃) δ 1.29 (s, 6H), 2.99 (m, 1H), 6.39 (s, 1H), 6.67(s, 1H), 7.08-7.32 (m, 6H), 7.99 (d, J=7 Hz, 1H), 8.34 (s, 1H), 8.45 (d,J=7 Hz, 1H); LC-MS (ESI) m/z 323 (M+H)⁺.

Example 350B: Using the procedure described in Example 306B, to asolution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (91 mg, 0.3mmol), prepared as described in Example 113A, in THF (2 ml) was addedDMAP (20 mg, 0.16 mmol) and phenyl3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate (110 mg, 0.34mmol), described in the previous step. The crude was purified by silicagel chromatography (DCM/MeOH 2-10%) to afford1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-yl)urea(91 mg, 58%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.22 (d, J=7 Hz,6H), 2.89 (m, 1H), 3.99 (s, 6H), 6.35 (s, 1H), 6.92 (d, J=7.8 Hz, 1H),7.19 (d, J=7.8 Hz, 1H), 7.34-7.39 (m, 2H), 7.52-7.55 (m, 3H), 7.97 (d,J=7.2 Hz, 1H), 8.55 (s, 1H), 8.58-8.60 (m, 2H), 8.77 (d, J=2.4 Hz, 1H),9.19 (s, 1H); LC-MS (ESI) m/z 526 (M+H)⁺.

Example 351 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-yl)urea

Using the procedure described in Example 306A, to a solution of3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (92 mg, 0.3 mmol), preparedas described in Example 115B, in THF (2 ml) was added DMAP (20 mg, 0.16mmol) and phenyl 3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate(106 mg, 0.33 mmol), described in Example 350A. The crude was purifiedby silica gel chromatography (DCM/MeOH 2-10%) to afford1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-isopropyl-1-(pyridin-3-yl)-1H-pyrazol-5-yl)urea(47 mg, 28%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.23 (d, J=7 Hz,6H), 2.90 (m, 1H), 3.99 (s, 6H), 6.36 (s, 1H), 7.24 (d, J=7.5 Hz, 1H),7.35 (d, J=4.8 Hz, 1H), 7.40-7.47 (m, 3H), 7.56 (dd, J=4.8, 1H), 7.77(s, 1H), 7.97 (d, J=8.1 Hz, 1H), 8.58 (d, J=4.8 Hz, 2H), 8.69 (s, 1H),8.78 (d, J=2.4 Hz, 1H), 9.19 (s, 1H); LC-MS (ESI) m/z 542 (M+H)⁺.

Example 352 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-ethyl-1-phenyl-1H-pyrazol-5-yl)urea

Example 352A Step 1: A stirred suspension of sodium hydride (12 g of a60% dispersion in mineral oil, 0.30 mol, which was washed with petroleumether twice in dry THF) in THF (100 mL) was heated to 75° C. To this wasadded a mixture of ethyl propionate (20.42 g, 0.20 mol) and dryacetonitrile (12.32 g, 0.30 mol), dropwise, and the resulting colorlesssuspension was heated at 70° C. for 24 h. After cooling to rt thereaction mixture was concentrated under reduced pressure and the residuepoured into water (100 mL) and extracted with ethyl acetate (100 mL).The aqueous layer was separated, acidified to pH 2 with aqueous 2 M HCland extracted with diethyl ether (2×200 mL). The combined diethyl etherlayers were dried over magnesium sulfate then concentrated under reducedpressure to afford 3-oxopentanenitrile as yellow oil (20 g) which wasused in the next step without further purification.

Example 352A Step 2: A stirred mixture of 3-oxopentanenitrile (19.42 g,0.20 mol) and phenylhydrazine (23.62 g, 0.20 mol) in ethanol (200 mL)was heated at 90° C. for 15 h. The reaction mixture was quenched withwater and extracted with dichloromethane. The combined dichloromethanelayers were dried over magnesium sulfate, concentrated under reducedpressure, and dried under vacuum to afford the light yellow oil whichwas purified by silica gel flash column chromatography (eluting with amixture of 20% ethyl acetate in petroleum ether). The obtained solid wasrecrystallized from a mixture of 10% petroleum ether in ethyl acetate,to afford 3-ethyl-1-phenyl-1H-pyrazol-5-amine (14 g, 37% over two steps)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.57-7.59 (m, 2H),7.43-7.46 (m, 2H), 7.27 (m, 1H), 5.36 (s, 1H), 5.26 (s, 2H), 2.45 (q,J=7.6 Hz, 2H), 1.15 (t, J=7.6 Hz, 3H); LC-MS (ESI) m/z 188 (M+H)⁺.

Example 352A Step 3: To a stirred mixture of3-ethyl-1-phenyl-1H-pyrazol-5-amine (1.00 g, 5.34 mmol) and potassiumcarbonate (1.48 g, 10.68 mmol) in THF (50 mL) at −5° C., was addedphenyl chloroformate (1.00 g, 6.41 mmol) dropwise. After stirring for afurther 30 min at −5° C., the reaction mixture it was warmed to rt andstirred for a further 15 h. The mixture was quenched with water andextracted with dichloromethane. The combined dichloromethane layers weredried over magnesium sulfate, concentrated under reduced pressure, anddried under vacuum to afford an oil. Recrystallization from petroleumether gave phenyl 3-ethyl-1-phenyl-1H-pyrazol-5-ylcarbamate (1.00 g,61%) as a colorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.07 (brs, 1H),6.74-7.59 (m, 10H), 6.30 (s, 1H), 2.60 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6Hz, 3H); LC-MS (ESI) m/z 308 (M+H)⁺.

Example 352B: A stirred mixture of phenyl3-ethyl-1-phenyl-1H-pyrazol-5-ylcarbamate (0.15 g, 0.50 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described inExample 113A) (0.15 g, 0.50 mmol) in DMSO (2 mL) was heated at 70° C.for 15 h. After cooling to rt, the reaction mixture was diluted withethyl acetate (50 mL) and washed with water (2×20 mL). The organic layerwas separated, dried over magnesium sulfate, and concentrated underreduced pressure to afford an oil. Purification via preparative silicagel thin-layer chromatography (eluting with a mixture of 8% methanol indichloromethane containing 0.5% ammonia) followed by recrystallizationfrom diethyl ether afforded1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-ethyl-1-phenyl-1H-pyrazol-5-yl)urea(80 mg, 32%) as a colorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.21 (s,1H), 8.55 (s, 1H), 8.50 (s, 1H), 7.52-7.55 (m, 6H), 7.34-7.42 (m, 3H),7.18 (m, 1H), 6.92 (m, 1H), 6.30 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H),2.56 (m, 2H), 1.19 (m, 3H); LC-MS (ESI) m/z 511 (M+H)⁺.

Example 353 Preparation of1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 353A Step 1: A stirred suspension of sodium hydride (5.47 g of a60% dispersion in mineral oil, 137 mmol) in THF (200 mL) was heated to75° C. To this was added a mixture of ethyl cyclopropanecarboxylate (10g, 88 mmol) and acetonitrile (5.62 g, 137 mmol), dropwise over thecourse of 30 min. The resulting suspension was heated at 70° C. for afurther 15 h. After cooling to rt, the reaction mixture was poured intowater and the resulting solution was extracted with ethyl ether. Theaqueous layer was separated, acidified to pH 2 with aqueous 2M HCl, andextracted with ethyl ether. The combined ether layers were dried overmagnesium sulfate and then concentrated under reduced pressure to give ayellow oil (10 g). The yellow oil was dissolved in a mixture of ethanol(200 mL) and phenylhydrazine (10.46 g, 97 mmol), and the resultingsolution was heated to reflux for 28 h. After cooling to rt, thereaction mixture was concentrated under reduced pressure and the residuewas washed with ethyl ether to afford3-cyclopropyl-1-phenyl-1H-pyrazol-5-amine (8.32 g, 47%) as a pale yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.56-7.57 (m, 2H), 7.43-7.47 (m, 2H),7.27 (m, 1H), 5.25 (s, 2H), 5.19 (s, 1H), 1.76 (m, 1H), 0.80-0.85 (m,2H), 0.60-0.63 (m, 2H).

Example 353A Step 2: To a stirred solution of3-cyclopropyl-1-phenyl-1H-pyrazol-5-amine (1.00 g, 5.03 mmol) andtriethylamine (0.66 g, 6.53 mmol) at rt, was added phenyl chloroformate(0.94 g, 6.01 mmol). The reaction mixture was stirred at rt for 15 h.The reaction mixture was partitioned between a mixture ofdichloromethane (20 mL) and water (20 mL) and the organic layer waswashed thrice with water, dried over sodium sulfate, filtered andconcentrated under reduced pressure to give yellow oil. Trituration withcyclohexane afforded phenyl3-cyclopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate (1.01 g, 63%) as acolorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.05 (s, 1H), 6.71-7.55(m, 10H), 6.18 (s, 1H), 1.92 (m, 1H), 0.91 (m, 2H), 0.73 (m, 2H).

Example 353B: A stirred mixture of phenyl3-cyclopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate (125 mg, 0.39 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described inExample 113A) (100 mg, 0.34 mmol) in DMSO (1 mL) was heated to 70° C.for 18 h. After cooling to rt, water (20 mL) was added. The resultingsuspension was filtered and the collected solid purified via preparativesilica gel thin-layer chromatography (eluting with a mixture of 10:10:1ethyl acetate: dichloromethane: methanol) to give a solid which wastriturated with diethyl ether (50 mL) to afford1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(58 mg, 33%) as a colorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.21 (s,1H), 8.55 (s, 1H), 8.49 (s, 1H), 7.51-7.55 (m, 6H), 7.34-7.39 (m, 3H),7.17 (m, 1H), 6.91 (m, 1H), 6.14 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H),1.86 (m, 1H), 0.86-0.88 (m, 2H), 0.65-0.67 (m, 2H); LC-MS (ESI) m/z 523(M+H)⁺.

Example 354 Preparation of1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

A stirred mixture of phenyl3-cyclopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate as described in Example353A (250 mg, 0.78 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline(prepared as described in Example 115B) (200 mg, 0.64 mmol) in DMSO (1mL) was heated to 40° C. for 48 h. After cooling to rt, water (20 mL)was added. The resulting suspension was filtered and the collected solidpurified via preparative silica gel thin-layer chromatography (elutingwith a mixture of 10:10:1 ethyl acetate: dichloromethane: methanol) togive a solid which was triturated with diethyl ether (50 mL) to afford1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(162 mg, 47%) as a colorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.21 (s,1H), 8.68 (s, 1H), 8.49 (s, 1H), 7.77 (s, 1H), 7.22-7.51 (m, 10H), 6.15(s, 1H), 3.99 (s, 6H), 1.86 (m, 1H), 0.85-0.91 (m, 2H), 0.65-0.68 (m,2H); LC-MS (ESI) m/z 539 (M+H)⁺.

Example 355 Preparation of1-(3-cyclobutyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 355A Step 1: A stirred suspension of sodium hydride (12 g of a60% dispersion in mineral oil, 0.30 mol, which was washed with petroleumether twice in dry THF) was heated to 75° C. To this was added a mixtureof ethyl cyclobutanecarboxylate (25.64 g, 0.20 mol) and dry acetonitrile(12.32 g, 0.30 mol), dropwise, and the resulting colorless suspensionwas heated at 70° C. for 24 h. After cooling to rt the reaction mixturewas concentrated under reduced pressure and the residue poured intowater (100 mL) and extracted with ethyl acetate (100 mL). The aqueouslayer was separated, acidified to pH 2 with aqueous 2 M HCl andextracted with diethyl ether (2×200 mL). The combined diethyl etherlayers were dried over magnesium sulfate then concentrated under reducedpressure to afford 3-cyclobutyl-3-oxopropanenitrile as yellow oil whichwas used in the next step without further purification.

Example 355A Step 2: A stirred mixture of3-cyclobutyl-3-oxopropanenitrile (24.6 g, 0.20 mol) and phenylhydrazine(23.62 g, 0.20 mol) in ethanol (200 mL) was heated at 90° C. for 15 h.The reaction mixture was quenched with water and extracted withdichloromethane. The combined dichloromethane layers were dried overmagnesium sulfate, concentrated under reduced pressure to give a solidwhich was triturated with a mixture of 10% petroleum ether in ethylacetate, followed by trituration with diethyl ether to afford3-cyclobutyl-1-phenyl-1H-pyrazol-5-amine (18.20 g, 43% over two steps)as a colorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.55-7.57 (m, 2H),7.42-7.46 (m, 2H), 7.26 (m, 1H), 5.40 (s, 1H), 5.25 (s, 2H), 3.33 (m,1H), 2.05-2.50 (m, 4H), 1.82-1.96 (m, 2H).

Example 355A Step 3: To a stirred mixture of3-cyclobutyl-1-phenyl-1H-pyrazol-5-amine (1.00 g, 4.69 mmol) andpotassium carbonate (1.48 g, 10.68 mmol) in THF (50 mL) at −5° C., wasadded phenyl chloroformate (0.88 g, 5.62 mmol) dropwise. After stirringfor a further 30 min at −5° C., the reaction mixture was warmed to rtand stirred for a further 15 h. The mixture was quenched with water andextracted with dichloromethane. The combined dichloromethane layers weredried over magnesium sulfate, concentrated under reduced pressure, anddried under vacuum to afford an oil. Recrystallization from petroleumether gave phenyl 3-cyclobutyl-1-phenyl-1H-pyrazol-5-ylcarbamate (1.30g, 83%) as a colorless solid. ¹H NMR (400 MHz, CDCl₃) δ 6.53-7.53 (m,12H), 3.57 (m, 1H), 2.26-2.38 (m, 4H), 1.64-2.07 (m, 2H); LC-MS (ESI)m/z 334 (M+H)⁺.

Example 355B:1-(3-cyclobutyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)ureawas prepared from phenyl 3-cyclobutyl-1-phenyl-1H-pyrazol-5-ylcarbamateand 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described inExample 113A) according to the procedure given in Example 352B. ¹H NMR(400 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.55 (s, 1H), 8.49 (s, 1H), 7.51-7.55(m, 6H), 7.34-7.42 (m, 3H), 7.18 (m, 1H), 6.92 (m, 1H), 6.36 (s, 1H),3.99 (s, 3H), 3.98 (s, 3H), 3.35 (m, 1H), 2.08-2.26 (m, 4H), 1.84-1.99(m, 2H); LC-MS (ESI) m/z 537 (M+H)⁺.

Example 356 Preparation of1-(3-cyclobutyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

1-(3-cyclobutyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)ureawas prepared from phenyl 3-cyclobutyl-1-phenyl-1H-pyrazol-5-ylcarbamateand 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as describedin Example 115B) according to the procedure given in Example 352B. ¹HNMR (400 MHz, DMSO-d₆) δ 9.24 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 7.78(s, 1H), 7.22-7.53 (m, 10H), 6.38 (m, 1H), 3.99 (s, 6H), 3.44 (m, 1H),2.14-2.50 (m, 4H), 1.23-1.99 (m, 2H); LC-MS (ESI) m/z 553 (M+H)⁺.

Example 357 Preparation of1-(1-benzyl-3-tert-butyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 357A step 1: Following the procedure in Example 161A Step 3,benzylhydrazine (977 mg, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile(1.0 g, 8.0 mmol) to give 1-benzyl-3-tert-butyl-1H-pyrazol-5-amine (666mg, 2.90 mmol, 36%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.32-7.21 (m, 3H), 7.09(d, 2H), 5.17 (s, 1H), 5.05 (d, 4H), 1.15 (s, 9H); LC-MS (ESI) m/z 230(M+H)⁺.

Example 357A step 2: Following the procedure in Example 118A,1-benzyl-3-tert-butyl-1H-pyrazol-5-amine (666 mg, 2.64 mmol) and phenylchloroformate (1.0 mL, 8.0 mmol) to give phenyl1-benzyl-3-tert-butyl-1H-pyrazol-5-ylcarbamate (565 mg, 1.62 mmol, 61%).¹H NMR (300 MHz, DMSO-d₆) δ 10.20 (br s, 1H), 7.43-7.10 (m, 10H), 6.14(s, 1H), 5.29 (s, 1H), 1.22 (s, 9H); LC-MS (ESI) m/z 350 (M+H)⁺.

Example 357B: The title compound was prepared from the carbamate fromthe previous step (105 mg, 0.30 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (90 mg, 0.30 mmol) using theprocedure in Example 115C to give1-(1-benzyl-3-tert-butyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(50 mg, 0.090 mmol, 30%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.59(br s, 2H), 7.58-6.93 (m, 11H), 6.16 (s, 1H), 5.20 (br s, 2H), 3.98 (s,6H), 1.21 (s, 9H); LC-MS (ESI) m/z 553 (M+H)⁺.

Example 358 Preparation of1-(1-benzyl-3-tert-butyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared from the carbamate in Example 357A (105mg, 0.30 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (95 mg,0.30 mmol) using the procedure in Example 115C to give1-(1-benzyl-3-tert-butyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(26 mg, 0.046 mmol, 15%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.68(s, 1H), 8.59 (s, 1H), 7.81 (s, 1H), 7.41-7.24 (m, 8H), 7.06 (br s, 2H),6.15 (s, 1H), 5.19 (br s, 2H), 3.98 (s, 6H), 1.21 (s, 9H); LC-MS (ESI)m/z 569 (M+H)⁺.

Example 359 Preparation of1-(3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 359A Step 1: The title compound was prepared from3-Fluorophenylhydrazine hydrochloride (1.30 g, 8.0 mmol) and4,4-Dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) using the procedurein Example 161A Step 3 to give3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-amine (1.24 g, 5.32 mmol,67%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.49-7.41 (m, 3H), 7.10 (br s, 1H),5.41 (s, 1H), 5.35 (br s, 2H), 1.21 (s, 9H); LC-MS (ESI) m/z 234 (M+H)⁺.

Example 359A Step 2: The title compound was prepared from3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-amine (1.24 mg, 5.32 mmol)and phenyl chloroformate (2.0 mL, 16.0 mmol) using the procedure inExample 118A to give phenyl3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-ylcarbamate (926 mg, 2.62mmol, 49%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.23 (s, 1H), 8.68 (s, 1H), 8.53(s, 1H), 7.79-7.23 (m, 8H), 6.38 (s, 1H), 1.27 (s, 9H); LC-MS (ESI) m/z354 (M+H)⁺.

Example 359B: The title compound was prepared from the carbamate fromthe previous step (105 mg, 0.30 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (90 mg, 0.30 mmol) using theprocedure in Example 115C to give1-(3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(39 mg, 0.070 mmol, 23%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.56(br s, 2H), 7.58-7.54 (m, 3H), 7.45-7.35 (m, 4H), 7.25-7.20 (m, 2H),6.92 (d, 1H), 6.39 (s, 1H), 3.99 (s, 6H), 1.27 (s, 9H); LC-MS (ESI) m/z557 (M+H)⁺.

Example 360 Preparation of1-(3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared from the carbamate in Example 359A (105mg, 0.30 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (95 mg,0.30 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(45 mg, 0.079 mmol, 26%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.69(s, 1H), 8.55 (s, 1H), 7.80 (s, 1H), 7.57-7.23 (m, 9H), 6.38 (s, 1H),4.01 (s, 6H), 1.27 (s, 9H); LC-MS (ESI) m/z 573 (M+H)⁺.

Example 361 Preparation of1-(3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 361A Step 1: The title compound was prepared from4-methoxyphenylhydrazine hydrochloride (1.39 g, 8.0 mmol) and4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) using the procedurein Example 161A Step 3 to give3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (1.24 g, 4.08 mmol,63%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.42 (d, 2H), 7.00 (d, 2H), 5.33 (s,1H), 5.05 (s, 2H), 1.20 (s, 9H); LC-MS (ESI) m/z 246 (M+H)⁺.

Example 361A Step 2: The title compound was prepared from3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (1.24 g, 5.06 mmol)and phenyl chloroformate (1.90 mL, 15.0 mmol) using the procedure inExample 118A to give phenyl3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-ylcarbamate (1.24 g, 3.40mmol, 67%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.96 (br s, 1H), 7.44-7.06 (m,9H), 6.31 (s, 1H), 3.81 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 366(M+H)⁺.

Example 361B: The title compound was prepared from the carbamate fromthe previous step (109 mg, 0.30 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.30 mmol) using theprocedure in Example 115C to give1-(3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(51 mg, 0.090 mmol, 30%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.55(s, 1H), 8.36 (s, 1H), 7.58-7.40 (m, 6H), 7.18-6.91 (m, 4H), 6.32 (s,1H), 3.99 (s, 6H), 3.81 (s, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 569(M+H)⁺.

Example 362 Preparation of1-(3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared from the carbamate in Example 361A (110mg, 0.30 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg,0.30 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(41 mg, 0.070 mmol, 23%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.68(s, 1H), 8.35 (s, 1H), 7.80 (s, 1H), 7.42-7.32 (m, 6H), 7.24 (d, 1H),7.08-7.06 (m, 2H), 6.32 (s, 1H), 3.98 (s, 6H), 3.81 (s, 3H), 1.24 (s,9H); LC-MS (ESI) m/z 585 (M+H)⁺.

Example 363 Preparation of1-(3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 363A Step 1: The title compound was prepared from3-chlorophenylhydrazine hydrochloride (1.43 g, 8.0 mmol) and4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) using the procedurein Example 161A Step 3 to give3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-amine (1.42 g, 5.70 mmol,71%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.67 (s, 1H), 7.61 (d, 1H), 7.46 (t,1H), 7.30 (d, 1H), 5.42 (s, 1H), 5.34 (s, 2H), 1.09 (s, 9H); LC-MS (ESI)m/z 250 (M+H)⁺.

Example 363A Step 2: The title compound was prepared from3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-amine (1.42 g, 5.69 mmol)and phenyl chloroformate (2.2 mL, 17.1 mmol) using the procedure inExample 118A to give phenyl3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-ylcarbamate (394 mg, 1.07mmol, 19%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.17 (br s, 1H), 7.62-7.58 (m,3H), 7.48-7.39 (m, 3H), 7.25 (t, 1H), 7.09 (br s, 2H), 6.40 (s, 1H),1.28 (s, 9H); LC-MS (ESI) m/z 370 (M+H)⁺.

Example 363B: The title compound was prepared from the carbamate fromthe previous step (111 mg, 0.30 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.30 mmol) using theprocedure in Example 115C to give1-(3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(65 mg, 0.11 mmol, 38%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.25 (s, 1H), 8.56(br s, 2H), 7.63-7.35 (m, 8H), 7.22 (d, 1H), 6.94 (d, 1H), 6.38 (s, 1H),3.99 (s, 6H), 1.27 (s, 9H); LC-MS (ESI) m/z 573 (M)⁺.

Example 364 Preparation of1-(3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared from the carbamate from Example 363A(111 mg, 0.30 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94mg, 0.30 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(101 mg, 0.17 mmol, 57%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.69(s, 1H), 8.56 (s, 1H), 7.80 (s, 1H), 7.63-7.26 (m, 6H), 6.39 (s, 1H),3.98 (s, 6H), 1.27 (s, 9H); LC-MS (ESI) m/z 589 (M)⁺.

Example 365 Preparation of1-(3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 365A Step 1: Following the procedure in Example 161A Step3,4-chlorophenylhydrazine hydrochloride (1.43 g, 8.0 mol) and4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) were reacted to give3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-amine (653 mg, 2.62 mmol,33%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.61 (d, 1H), 7.49 (d, 2H), 5.39 (s,1H), 5.28 (s, 1H), 1.09 (s, 9H); LC-MS (ESI) m/z 250 (M+H)⁺.

Example 365A Step 2: Following the procedure in Example 118A,3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-amine (653 mg, 2.62 mmol)and phenyl chloroformate (1.0 mL, 7.85 mmol) were reacted to give phenyl3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-ylcarbamate (575 mg, 1.56mmol, 59%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.19 (br s, 1H), 7.63-7.60 (m,4H), 7.39-7.36 (m, 2H), 7.23 (t, 1H), 7.06 (br s, 2H), 6.38 (s, 1H),1.28 (s, 9H); LC-MS (ESI) m/z 370 (M+H)⁺.

Example 365B: The title compound was prepared from the carbarmate fromthe previous step (111 mg, 0.30 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.30 mmol) using theprocedure in Example 115C to give1-(3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(82 mg, 0.14 mmol, 48%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.20 (s, 1H),8.55-8.49 (m, 2H), 7.60-7.54 (m, 6H), 7.39-7.34 (m, 2H), 7.18 (d, 1H),6.92 (d, 1H), 6.35 (s, 1H), 3.99 (s, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z573 (M)⁺.

Example 366 Preparation of1-(3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared from the carbamate in Example 365A (111mg, 0.30 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg,0.30 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(65 mg, 0.11 mmol, 37%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.68(s, 1H), 8.49 (s, 1H), 7.79 (s, 1H), 7.57 (br s, 4H), 7.48-7.22 (m, 5H),6.36 (s, 1H), 3.98 (s, 6H), 1.26 (s, 9H); LC-MS (ESI) m/z 589 (M+H)⁺.

Example 367 Preparation of1-(5-tert-butylisoxazol-3-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea

Example 367A: To a stirred suspension of phenyl5-tert-butylisoxazol-3-ylcarbamate (prepared as described in Example270A) (260 mg, 1 mmol) and 3-amino-4-fluorophenol (127 mg, 1 mmol) inacetonitrile (15 mL) at rt, was added DBU (0.3 mL, 2 mmol). The mixturewas heated at 50° C. for 1 h. The reaction mixture was cooled to rt,concentrated under reduced pressure, and the residue purified via silicagel column chromatography to afford1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-hydroxyphenyl)urea (200 mg,68%) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.68 (m, 2H), 8.41 (m, 1H),7.68 (m, 1H), 6.56-6.65 (m, 2H), 6.45 (s, 1H), 1.29 (s, 9H); LC-MS (ESI)m/z 294 (M+H)⁺.

Example 367B: To a stirred solution of1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-hydroxyphenyl)urea (200 mg,0.68 mmol) and 4-chloro-6,7-dimethoxyquinazoline (153 mg, 0.68 mmol) inDMF (4 mL) at rt, was added potassium carbonate (188 mg, 1.36 mmol). Thereaction mixture was stirred at 35° C. for 15 h. The mixture was pouredinto water, and the resulting brown solid was filtrated, washed withwater, and dried to afford the crude product. Purification viareverse-phase preparative HPLC afforded1-(5-tert-butylisoxazol-3-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea(25 mg, 8%) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.86 (brs, 1H), 8.85(brs, 1H), 8.57 (s, 1H), 8.16 (m, 1H), 7.55 (s, 1H), 7.40-7.44 (m, 2H),7.16 (m, 1H), 6.50 (s, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 1.30 (s, 9H);LC-MS (ESI) m/z 482 (M+H)⁺.

Example 368 Preparation of1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea

Example 368A: To a stirred suspension of phenyl3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared as described inexample 153A) (335 mg, 1 mmol) and 3-amino-4-fluorophenol (127 mg, 1mmol) in acetonitrile (15 mL) at rt, was added DBU (0.3 mL, 2 mmol). Themixture was heated at 50° C. for 1 h. The reaction mixture was cooled tort, concentrated under reduced pressure, and the residue purified viasilica gel column chromatography to afford1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-hydroxyphenyl)urea(217 mg, 59%) as a solid. LC-MS (ESI) m/z 369 (M+H)⁺.

Example 368B: To a stirred solution of1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-hydroxyphenyl)urea(217 mg, 0.59 mmol) and 4-chloro-6,7-dimethoxyquinazoline (132 mg, 0.59mmol) in DMF (4 mL) at rt, was added potassium carbonate (163 mg, 1.18mmol). The reaction mixture was stirred at 35° C. for 15 h. The mixturewas poured into water, and the resulting brown solid was filtrated,washed with water, and dried to afford the crude product. Purificationvia reverse-phase preparative HPLC afforded1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea(19 mg, 6%) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (brs, 1H), 8.89(brs, 1H), 8.57 (s, 1H), 8.16 (m, 1H), 7.53-7.59 (m, 5H), 7.37-7.46 (m,3H), 7.15 (m, 1H), 6.43 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 1.29 (s,9H); LC-MS (ESI) m/z 557 (M+H)⁺.

Example 369 Preparation of1-(3-tert-butyl-1-(4-tert-butylphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 369A Step 1: Using the procedure in Example 161A Step 3,4-tert-butylphenyl-hydrazine monohydrochloride (1.00 g, 4.98 mmol) and4,4-dimethyl-3-oxopentanenitrile (625 mg, 4.98 mmol) were reacted togive 3-tert-butyl-1-(4-tert-butylphenyl)-1H-pyrazol-5-amine (996 mg,3.67 mmol, 51%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.46 (br s, 4H), 5.35 (s,1H), 5.15 (br s, 2H), 1.30 (s, 9H), 1.20 (s, 9H); LC-MS (ESI) m/z 272(M+H)⁺.

Example 369A Step 2: Using the procedure in Example 118A,3-tert-butyl-1-(4-tert-butylphenyl)-1H-pyrazol-5-amine (996 mg, 3.67mmol) and phenyl chloroformate (1.40 mL, 11.0 mmol) were reacted to givephenyl 3-tert-butyl-1-(4-tert-butylphenyl)-1H-pyrazol-5-ylcarbamate (957mg, 2.45 mmol, 66%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.05 (br s, 1H),7.56-7.08 (m, 8H), 6.77 (s, 1H), 6.33 (s, 1H), 1.33 (s, 9H), 1.28 (s,9H); LC-MS (ESI) m/z 392 (M+H)⁺.

Example 369B: The title compound was prepared from the carbamate fromthe previous step (117 mg, 0.30 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.30 mmol) using theprocedure in Example 115C to give1-(3-tert-butyl-1-(4-tert-butylphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(86 mg, 0.14 mmol, 48%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.23 (s, 1H), 8.55(s, 1H), 8.49 (s, 1H), 7.58-7.34 (m, 8H), 7.18 (d, 1H), 6.93 (d, 1H),6.35 (s, 1H), 3.99 (s, 6H), 1.32 (s, 9H); LC-MS (ESI) m/z 595 (M+H)⁺.

Example 370 Preparation of1-(3-tert-butyl-1-(4-tert-butylphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared from the carbamate described in Example369A (117 mg, 0.30 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline(94 mg, 0.30 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-(4-tert-butylphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(104 mg, 0.17 mmol, 57%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.23 (s, 1H), 8.68(s, 1H), 8.48 (s, 1H), 7.81 (s, 1H), 7.55-7.33 (m, 8H), 7.24 (d, 1H),6.35 (s, 1H), 3.98 (s, 6H), 1.32 (s, 9H); LC-MS (ESI) m/z 611 (M+H)⁺.

Example 371 Preparation of1-(3-tert-butyl-1-(2-fluorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

Example 371A Step 1: using the procedure in Example 161A Step 3,2-fluorophenylhydrazine hydrochloride (1.30 g, 8.0 mmol) and4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) were reacted to give3-tert-butyl-1-(2-fluorophenyl)-1H-pyrazol-5-amine (1.23 g, 5.28 mmol,66%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.46-7.29 (m, 4H), 5.31 (s, 1H), 5.05(br s, 2H), 1.20 (s, 9H); LC-MS (ESI) m/z 234 (M+H)⁺.

Example 371A Step 2: Using the procedure in Example 118A,3-tert-butyl-1-(2-fluorophenyl)-1H-pyrazol-5-amine (1.23 g, 5.27 mmol)and phenyl chloroformate (2.0 mL, 16.0 mmol) were reacted to give phenyl3-tert-butyl-1-(2-fluorophenyl)-1H-pyrazol-5-ylcarbamate (1.21 g, 3.42mmol, 59%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.13 (s, 1H), 7.55-7.35 (m,6H), 7.23 (t, 1H), 7.08 (br s, 2H), 6.34 (s, 1H), 1.29 (s, 9H); LC-MS(ESI) m/z 354 (M+H)⁺.

Example 371B: The title compound was prepared from the carbamate inprevious step (105 mg, 0.30 mmol) and3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (95 mg, 0.30 mmol) using theprocedure in Example 115C to give1-(3-tert-butyl-1-(2-fluorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(54 mg, 0.094 mmol, 31%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.68(s, 1H), 8.44 (s, 1H), 7.79 (s, 1H), 7.58-7.32 (m, 8H), 7.24 (d, 1H),6.37 (s, 1H), 3.98 (s, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 573 (M+H)⁺.

Example 372 Preparation of1-(3-tert-butyl-1-(2-fluorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

The title compound was prepared from the carbamate described in Example371A (105 mg, 0.30 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline(90 mg, 0.30 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-(2-fluorophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(58 mg, 0.10 mmol, 35%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.55(s, 1H), 8.45 (s, 1H), 7.57-7.39 (m, 8H), 7.16 (s, 1H), 6.94 (s, 1H),6.37 (s, 1H), 3.99 (s, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 557 (M+H)⁺.

Example 373 Preparation of1-(3-tert-butyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 373A Step 1: The title compound was prepared from4-(trifluoromethyl)-phenylhydrazine (1.41 g, 8.0 mmol) and4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) using the procedurein Example 161A Step 3 to give to give3-tert-butyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (1.36 g,4.81 mmol, 60%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.81 (d, 2H), 7.80 (d, 2H),5.44 (s, 3H), 1.22 (s, 9H); LC-MS (ESI) m/z 284 (M+H)⁺.

Example 373A Step 2: The title compound was prepared from3-tert-butyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (1.36 g,4.80 mmol) and phenyl chloroformate (1.82 mL, 14.4 mmol) using theprocedure in Example 118A to give phenyl3-tert-butyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-ylcarbamate (113mg, 2.80 mmol, 58%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.20 (br s, 1H), 7.93(d, 2H), 7.81 (d, 2H), 7.40-7.10 (m, 5H), 6.44 (s, 1H), 1.29 (s, 9H);LC-MS (ESI) m/z 404 (M+H)⁺.

Example 373B: The title compound was prepared from the carbamate fromthe previous step (114 mg, 0.28 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (84 mg, 0.28 mmol) using theprocedure in Example 115C to give1-(3-tert-butyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(117 mg, 0.19 mmol, 69%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.23 (s, 1H), 8.63(s, 1H), 8.55 (s, 1H), 7.91-7.79 (m, 4H), 7.55 (br s, 2H), 7.40-7.35 (m,2H), 7.21 (d, 1H), 6.94 (d, 1H), 6.41 (s, 1H), 3.98 (s, 6H), 1.24 (s,9H); LC-MS (ESI) m/z 607 (M+H)⁺.

Example 374 Preparation of1-(3-tert-butyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared from the carbamate described in Example373A (121 mg, 0.30 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline(94 mg, 0.30 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(41 mg, 0.066 mmol, 22%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.24 (s, 1H), 8.68(s, 1H), 8.62 (s, 1H), 7.90-7.79 (m, 5H), 7.49-7.23 (m, 5H), 6.41 (s,1H), 3.98 (s, 6H), 1.28 (s, 9H); LC-MS (ESI) m/z 623 (M+H)⁺.

Example 375 Preparation of1-(3-tert-butyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

Example 375A Step 1: The title compound was prepared from2-(trifluoromethyl)-phenylhydrazine (1.41 g, 8.0 mmol) and4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) using the procedurein Example 161A Step 3 to give3-tert-butyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (1.45 g,5.12 mmol, 64%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.86 (d, 1H), 7.75 (t, 1H),7.65 (t, 1H), 7.49 (d, 1H), 5.27 (s, 1H), 4.97 (s, 1H), 1.18 (s, 9H);LC-MS (ESI) m/z 284 (M+H)⁺.

Example 375A Step 2: The title compound was prepared from3-tert-butyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (1.45 g,5.12 mmol) and phenyl chloroformate (1.95 mL, 15.4 mmol) using theprocedure in Example 118A to give phenyl3-tert-butyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5-ylcarbamate(1.46 g, 3.62 mmol, 71%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.20 (br s, 1H),7.92 (d, 1H), 7.85 (t, 1H), 7.74 (t, 1H), 7.54 (d, 1H), 7.38-7.36 (m,2H), 7.23 (t, 1H), 7.09 (br s, 2H), 6.32 (s, 1H), 1.25 (s, 9H); LC-MS(ESI) m/z 404 (M+H)⁺.

Example 375B: The title compound was prepared from the carbamate fromthe previous step (121 mg, 0.30 mmol) and3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.30 mmol) using theprocedure in Example 115C to give1-(3-tert-butyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(120 mg, 0.19 mmol, 64%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.69(s, 1H), 8.33 (s, 1H), 7.99-7.79 (m, 4H), 7.63 (d, 1H), 7.41-7.24 (m,5H), 6.34 (s, 1H), 3.98 (s, 6H), 1.23 (s, 9H); LC-MS (ESI) m/z 623(M+H)⁺.

Example 376 Preparation of1-(3-tert-butyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

The title compound was prepared from the carbamate in Example 375A (114mg, 0.28 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (84 mg,0.28 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(101 mg, 0.17 mmol, 59%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.55(s, 1H), 8.33 (s, 1H), 7.98 (d, 1H), 7.89-7.80 (m, 2H), 7.64-7.54 (m,3H), 7.39-7.33 (m, 2H), 7.12 (d, 1H), 6.93 (d, 1H), 6.33 (s, 1H), 3.99(s, 6H), 1.23 (s, 9H); LC-MS (ESI) m/z 607 (M+H)⁺.

Example 377 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

Example 377A Step 1: A mixture of3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile (1 g, 5.65 mmol)(prepared as described in example 137A step 1), hydroxylamine sulfate(1.11 g, 6.78 mmol) and sodium hydrogencarbonate (1.2 g, 14.13 mmol) ina mixture of 10% methanol in water (20 mL), was heated at 65° C. for 15h. After cooling to rt, the mixture was adjusted to pH 1 withconcentrated hydrochloric acid and separated into two equal 10 mLbatches and placed into two separate 20 mL microwave vials fitted with astirrer bar. After sealing, each batch was placed in a Biotage MicrowaveSynthesizer and heated (with stirring) at 140° C. for 5 min. Each batchwas cooled and neutralized with saturated aqueous sodiumhydrogencarbonate solution. Both processed batches were combined andconcentrated in vacuo and the aqueous solution extracted, twice, withdichloromethane. The combined organic layers were washed with brine,separated, dried over MgSO₄ and filtered. Concentration in vacuoafforded 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-amine (687 mg,64%) as a light yellow solid which taken on without furtherpurification. LC-MS (ESI) m/z 193 (M+H)⁺.

Example 377A Step 2: To a stirred mixture of5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-amine (687 mg, 3.58 mmol)and potassium carbonate (987 mg, 7.0 mmol) in dry dichloromethane (30mL) at 0° C., was added a solution of phenyl chloroformate (848 mg, 5.42mmol) in anhydrous dichloromethane (5 mL). The reaction mixture waswarmed to room temperature and stirred for a further 15 h. The reactionmixture was filtered and the filtrate concentrated under reducedpressure to give an oil. Purification via silica gel flashchromatography afforded phenyl5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-ylcarbamate (727 mg, 65%)as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 11.34 (brs, 1H),7.40-7.47 (m, 2H), 7.20-7.31 (m, 3H), 6.80 (s, 1H), 1.45-1.56 (m, 4H);LC-MS (ESI) m/z 313 (M+H)⁺.

Example 377B: The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (90 mg, 0.3 mmol) and thecarbamate from the previous step (112 mg, 0.36 mmol) using the procedurein Example 115C to give1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea(107 mg, 0.21 mmol, 69%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.73 (s, 1H), 9.10(s, 1H), 8.56 (s, 1H), 7.58 (s, 1H), 7.57 (s, 1H), 7.41 (t, 1H), 7.39(s, 1H), 7.26 (d, 1H), 6.98 (d, 1H), 6.85 (s, 1H), 3.99 (s, 3H), 3.98(s, 3H), 1.56-1.41 (m, 4H); LC-MS (ESI) m/z 516 (M+H)⁺.

Example 378 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea

The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (95 mg, 0.3 mmol) and thecarbamate in Example 377A (112 mg, 0.36 mmol) using the procedure inExample 115C to give1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea(108 mg, 0.20 mmol, 68%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.73 (s, 1H), 9.01(s, 1H), 8.69 (s, 1H), 7.84 (s, 1H), 7.52 (d, 1H), 7.45 (t, 1H), 7.35(s, 1H), 7.34 (s, 1H), 7.29 (d, 1H), 6.86 (s, 1H), 3.99 (s, 6H),1.56-1.45 (m, 4H); LC-MS (ESI) m/z 532 (M+H)⁺.

Example 379 Preparation of1-(3-tert-butyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 379A Step 1: Following the procedure in Example 161A Step3,3-trifluoromethylphenylhydrazine hydrochloride (781 mg, 4.44 mmol) and4,4-Dimethyl-3-oxopentanenitrile (500 mg, 4.0 mmol) were reacted to give3-tert-butyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (344 mg,1.21 mmol, 30%). No NMR taken. LC-MS (ESI) m/z 284 (M+H)⁺.

Example 379A Step 2: Following the procedure in Example 118A,3-tert-butyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (344 mg,1.21 mmol) and phenyl chloroformate (0.25 mL, 1.82 mmol) were reacted togive phenyl3-tert-butyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-ylcarbamate (119mg, 0.42 mmol, 35%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.05 (s, 1H),7.62-7.50 (m, 3H), 7.58-7.43 (m, 3H), 7.23 (t, 1H), 7.12 (br s, 2H),6.39 (s, 1H), 1.29 (s, 9H); LC-MS (ESI) m/z 404 (M+H)⁺.

Example 379B: The title compound was prepared from the carbamate fromthe previous step (114 mg, 0.28 mmol) and3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (84 mg, 0.28 mmol) using theprocedure in Example 115C to give1-(3-tert-butyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(107 mg, 0.18 mmol, 63%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.23 (s, 1H), 8.55(br s, 2H), 7.87 (br s, 2H), 7.75 (br s, 2H), 7.51 (d, 2H), 7.36 (t,2H), 7.18 (d, 1H), 6.91 (d, 1H), 6.38 (s, 1H), 3.97 (s, 6H), 1.27 (s,9H); LC-MS (ESI) m/z 607 (M+H)⁺.

Example 380 Preparation of1-(3-tert-butyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared from the carbamate in Example 379A (121mg, 0.30 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg,0.30 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(105 mg, 0.17 mmol, 56%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.24 (s, 1H), 8.68(s, 1H), 8.57 (s, 1H), 7.88 (s, 2H), 7.75 (br s, 3H), 7.45-7.23 (m, 5H),6.39 (s, 1H), 3.98 (s, 6H), 1.28 (s, 9H); LC-MS (ESI) m/z 623 (M+H)⁺.

Example 381 Preparation of1-(3-(2-cyanopropan-2-yl)isoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea

A mixture of phenyl 3-(2-cyanopropan-2-yl)isoxazol-5-ylcarbamate(prepared as described in Example 125A steps 1 through 3) (95 mg, 0.35mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared asdescribed in Example 115B) (100 mg, 0.319 mmol) andN,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) wasstirred at rt for 15 h. The reaction mixture was concentrated underreduced pressure to give the crude product which was partitioned betweendichloromethane (10 mL) and water (10 mL). The organic layer wasseparated and dried over magnesium sulfate. Concentration under reducedpressure gave a solid which was triturated with methanol to afford1-(3-(2-cyanopropan-2-yl)isoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea(50 mg, 32%) as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.52(brs, 1H), 9.14 (brs, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.57 (m, 1H),7.46 (m, 1H), 7.30-7.36 (m, 3H), 6.28 (s, 1H), 3.99 (s, 6H), 1.68 (s,6H); LC-MS (ESI) m/z 491 (M+H)⁺.

Example 382 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea

Example 382A: To a solution of 3-(trifluoromethyl)isoxazol-5-amine (165mg, 1.08 mmol) described in Example 229A and potassium carbonate (359mg, 2.6 mmol) in anhydrous THF (3 ml) was added dropwise 4-chlorophenylchloroformate (763 mg, 4 mmol) as a solution in THF (2 ml). The reactionmixture was stirred at rt overnight. The solvent was removed and theresidue taken in DCM, washed with water and brine and the organicscombined, dried (MgSO₄) and concentrated. The crude was purified bysilica gel chromatography (hexane/ethyl acetate 9:1) to afford phenyl4-chlorophenyl 3-(trifluoromethyl)isoxazol-5-ylcarbamate (239 mg, 78%)as a solid. ¹H NMR (300 MHz, CDCl₃) δ 5.95 (s, 1H), 6.93 (d, J=9 Hz,2H), 7.15 (d, J=9 Hz, 2H), 8.91 (brs, 1H).

Example 382B: To a solution of3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (92 mg, 0.3 mmol), preparedas described in Example 115B, in THF (3 ml) was added DMAP (18 mg, 0.15mmol) and phenyl 4-chlorophenyl3-(trifluoromethyl)isoxazol-5-ylcarbamate (92 mg, 0.33 mmol) describedin the previous step. Concentration under reduced pressure gave aresidue which was triturated with anhydrous diethyl ether and MeOH toafford1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea(112 mg, 76%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 3.76 (s, 6H), 6.49(s, 1H), 7.31-7.36 (m, 3H), 7.44-7.49 (m, 2H), 7.59 (d, J=6 Hz, 1H),7.86 (s, 1H), 8.70 (s, 1H), 9.31 (s, 1H); LC-MS (ESI) m/z 492 (M+H)⁺.

Example 383 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea

The title compound was prepared from3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol) and thecarbamate from Example 137A (116 mg, 0.3 mmol) using the procedure inExample 115C to give1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea(160 mg, 0.26 mmol, 88%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 8.69(s, 1H), 8.61 (s, 1H), 7.79 (s, 1H), 7.58-7.50 (m, 4H), 7.49-7.38 (m,3H), 7.34 (d, 2H), 7.25 (d, 1H), 6.56 (s, 1H), 3.99 (s, 6H), 1.35-1.29(m, 4H); LC-MS (ESI) m/z 607 (M+H)⁺.

Example 384 Preparation of1-(3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

Example 384A: To a stirred slurry of cesium carbonate (2.99 g, 9.20mmol) in anhydrous THF (50 mL) at rt, was added 3-aminophenol (1.00 g,9.17 mmol). After stirring for 30 mins,4-chloro-7-ethoxy-6-methoxyquinazoline (prepared as described in Example6A Steps 1 through 5) (2.19 g, 9.20 mmol) was added and the reactionmixture was heated at 50° C. for 18 h. The mixture was cooled to rt andconcentrated under reduced pressure and the resulting solid was washedwith water (three times) then ethyl acetate (three times) to afford3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)aniline (1.75 g, 61%) as yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (s, 1H), 7.51 (s, 1H), 7.35 (s,1H), 7.09 (m, 1H), 6.37-6.50 (m, 3H), 5.31 (brs, 2H), 4.25 (q, J=7 Hz,2H), 3.97 (s, 3H), 1.44 (t, J=7 Hz, 3H); LC-MS (ESI) m/z 312 (M+H)⁺.

Example 384B: The title compound was prepared from the carbamatedescribed in Example 161A or B (70 mg, 0.20 mmol) and the aniline fromthe previous step (62 mg, 0.20 mmol) using the procedure in Example 115Cto give1-(3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea(30 mg, 0.053 mmol, 26%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.31 (s, 1H), 8.80(s, 1H), 8.54 (s, 1H), 7.62-7.54 (m, 7H), 7.41-7.35 (m, 2H), 7.20 (d,1H), 6.94 (d, 1H), 6.87 (s, 1H), 4.26 (q, 2H), 3.98 (s, 6H), 1.44 (t,3H); LC-MS (ESI) m/z 565 (M+H)⁺.

Example 385 Preparation of1-(3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea

The title compound was prepared from the aniline described in Example384A (62 mg, 0.2 mmol) and Example 42A (78 mg, 0.26 mmol) using theprocedure in Example 115C to give1-(3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea(73 mg, 0.15 mmol, 76%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.38 (s, 1H), 9.09(s, 1H), 8.55 (s, 1H), 7.55 (m, 2H), 7.42 (t, 1H), 7.37 (s, 1H), 7.31(d, 1H), 7.00 (d, 1H), 6.15 (s, 1H), 4.26 (q, 2H), 3.99 (s, 3H), 1.66(d, 6H), 1.44 (t, 3H); LC-MS (ESI) m/z 482 (M+H)⁺.

Example 386 Preparation of1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)phenyl)urea

The title compound was prepared from the carbamate described in Example162A (60 mg, 0.20 mmol) and the aniline described in Example 384A (62mg, 0.20 mmol) using the procedure in Example 115C to give1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)phenyl)urea(28 mg, 0.055 mmol, 27%). ¹H NMR (300 MHz, MeOD) δ 8.49 (s, 1H),7.62-7.59 (m, 2H), 7.41 (t, 1H), 7.32-7.28 (m, 2H), 7.00 (d, 1H), 6.66(s, 1H), 4.69 (s, 2H), 4.54 (s, 2H), 4.26 (q, 2H), 4.03 (s, 3H), 1.53(t, 3H); LC-MS (ESI) m/z 514 (M+H)⁺.

Example 387 Preparation of1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)phenyl)urea

The title compound was prepared using the carbamate described in Example153A (67 mg, 0.20 mmol) and the aniline described in Example 384A (62mg, 0.2 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)phenyl)urea(42 mg, 0.076 mmol, 38%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.54(s, 1H), 8.45 (s, 1H), 7.56-7.52 (m, 6H), 7.39-7.35 (m, 3H), 7.17 (d,1H), 6.91 (d, 1H), 6.35 (s, 1H), 4.26 (q, 2H), 3.97 (s, 3H), 1.45 (t,3H), 1.26 (s, 9H); LC-MS (ESI) m/z 553 (M+H)⁺.

Example 388 Preparation of1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(7-ethoxy-6-methoxyquinazolin-4-ylthio)phenyl)urea

Example 388A: To a stirred slurry of sodium hydride (350 mg of a 60%dispersion in mineral oil, 8.80 mmol) in anhydrous THF (50 mL) at rt,was added 3-aminobenzenethiol (1.00 g, 9.17 mmol). After stirring for 30mins, 4-chloro-7-ethoxy-6-methoxyquinazoline (prepared as described inExample 6A Steps 1 through 5) (1.91 g, 8.03 mmol) was added and thereaction mixture was stirred at rt for a further 4 h. The mixture wasconcentrated under reduced pressure and the resulting solid was washedwith water (three times) then ethyl acetate (three times) to afford3-(7-ethoxy-6-methoxyquinazolin-4-ylthio)aniline (2.36 g, 90%) as yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 7.30-7.31 (m, 2H), 7.13(m, 1H), 6.80 (s, 1H), 6.72-6.74 (m, 2H), 5.31 (brs, 2H), 4.25 (q, J=7Hz, 2H), 3.97 (s, 3H), 1.43 (t, J=7 Hz, 3H); LC-MS (ESI) m/z 328 (M+H)⁺.

Example 388B: The title compound was prepared using the carbamate inExample 162A (60 mg, 0.20 mmol) and the aniline from the previous step(66 mg, 0.20 mmol) using the procedure in Example 115C to give1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(7-ethoxy-6-methoxyquinazolin-4-ylthio)phenyl)urea(61 mg, 0.12 mmol, 57%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.70 (s, 1H), 9.02(s, 1H), 8.68 (s, 1H), 7.84 (s, 1H), 7.51-7.27 (m, 5H), 6.78 (s, 1H),4.71 (s, 2H), 4.56 (s, 2H), 4.25 (q, 2H), 3.99 (s, 3H), 1.43 (t, 3H),1.32 (s, 3H); LC-MS (ESI) m/z 530 (M+H)⁺.

Example 389 Preparation of1-(3-(7-ethoxy-6-methoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea

The title compound was prepared from the aniline described in Example388A (65 mg, 0.2 mmol) and the carbamate from Example 42A (78 mg, 0.26mmol) using the procedure in Example 115C to give1-(3-(7-ethoxy-6-methoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea(81 mg, 0.16 mmol, 81%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.40 (s, 1H), 9.10(s, 1H), 8.68 (s, 1H), 7.84 (s, 1H), 7.56 (d, 1H), 7.46 (t, 1H),7.34-7.29 (m, 3H), 6.16 (s, 1H), 4.26 (q, 2H), 3.99 (s, 3H), 1.66 (d,6H), 1.43 (t, 3H); LC-MS (ESI) m/z 498 (M+H)⁺.

Example 390 Preparation of1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)phenyl)urea

The title compound was prepared from the carbamate described in Example153A (67 mg, 0.20 mmol) and the aniline described in Example 260B (62mg, 0.20 mmol) using the procedure in Example 115C to give1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)phenyl)urea(47 mg, 0.085 mmol, 43%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 8.58(s, 1H), 8.46 (s, 1H), 7.60-7.50 (m, 6H), 7.45-7.36 (m, 3H), 7.20 (d,1H), 6.89 (d, 1H), 6.42 (s, 1H), 4.25 (q, 2H), 3.98 (s, 3H), 1.43 (t,3H), 1.24 (s, 9H); LC-MS (ESI) m/z 553 (M+H)⁺.

Example 391 Preparation of1-(3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

The title compound was prepared from the carbamate described in Example161 A or B (70 mg, 0.20 mmol) and the aniline described in Example 260B(62 mg, 0.20 mmol) using the procedure in Example 115C to give1-(3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea(39 mg, 0.069 mmol, 35%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 8.78(s, 1H), 8.54 (s, 1H), 7.60-7.50 (m, 6H), 7.45-7.36 (m, 2H), 7.20 (d,1H), 6.94 (d, 1H), 6.86 (s, 1H), 4.24 (q, 2H), 3.99 (s, 3H), 1.42 (t,3H); LC-MS (ESI) m/z 565 (M+H)⁺.

Example 392 Preparation of1-(3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea

The title compound was prepared from the aniline described in Example260B (62 mg, 0.2 mmol) and the carabamate described in Example 42A (78mg, 0.26 mmol) using the procedure in Example 115C to give1-(3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea(72 mg, 0.15 mmol, 75%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.38 (s, 1H), 9.09(s, 1H), 8.56 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.42 (t, 1H), 7.39(s, 1H), 7.31 (d, 1H), 6.99 (d, 1H), 6.15 (s, 1H), 4.24 (q, 2H), 4.00(s, 3H), 1.66 (d, 6H), 1.43 (t, 3H); LC-MS (ESI) m/z 482 (M+H)⁺.

Example 393 Preparation of1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)phenyl)urea

The title compound was prepared from the carbamate described in Example162A (60 mg, 0.20 mmol) and the aniline described in Example 260B (62mg, 0.20 mmol) using the procedure in Example 115C to give1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)phenyl)urea(32 mg, 0.062 mmol, 31%). ¹H NMR (300 MHz, MeOD) δ 8.45 (s, 1H),7.57-7.55 (m, 2H), 7.38-7.35 (m, 2H), 7.29-7.24 (m, 2H), 6.97-6.93 (m,2H), 6.64 (s, 1H), 4.67 (s, 2H), 4.52 (s, 2H), 4.20 (q, 2H), 4.01 (s,3H), 1.49 (t, 3H), 1.38 (s, 3H); LC-MS (ESI) m/z 514 (M+H)⁺.

Example 394 Preparation of1-(3-(6-ethoxy-7-methoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea

The title compound was prepared from the aniline described in Example262A (65 mg, 0.2 mmol) and the carbamate in Example 42A (78 mg, 0.26mmol) using the procedure in Example 115C to give1-(3-(6-ethoxy-7-methoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea(71 mg, 0.14 mmol, 71%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.40 (s, 1H), 9.09(s, 1H), 8.69 (s, 1H), 7.84 (s, 1H), 7.58-7.23 (m, 5H), 6.16 (s, 1H),4.26 (q, 2H), 3.99 (s, 3H), 1.66 (d, 6H), 1.44 (t, 3H); LC-MS (ESI) m/z498 (M+H)⁺.

Example 395 Preparation of1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(6-ethoxy-7-methoxyquinazolin-4-ylthio)phenyl)urea

The title compound was prepared from the carbamate described in Example162A (60 mg, 0.20 mmol) and the aniline described in Example 262A (66mg, 0.20 mmol) using the procedure in Example 115C to give1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(6-ethoxy-7-methoxyquinazolin-4-ylthio)phenyl)urea(50 mg, 0.095 mmol, 47%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.69 (s, 1H), 9.01(s, 1H), 8.68 (s, 1H), 7.84 (s, 1H), 7.52-7.27 (m, 5H), 6.77 (s, 1H),4.71 (s, 2H), 4.54 (s, 2H), 4.23 (q, 2H), 3.99 (s, 3H), 1.43 (t, 3H),1.34 (s, 3H); LC-MS (ESI) m/z 530 (M+H)⁺.

Example 396 Preparation of(1-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

1-(3-(6-Methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)ureawas obtained following the procedure described in Example 274B forsynthesis of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea,substituting phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate withphenyl 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate in Example161, and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline with3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)aniline in Example250 (0.075 g, 32%). ¹H NMR (300 MHz, DMSO-d₆) δ 2.80 (t, 2H), 3.34 (m,4H), 3.60 (m, 4H), 3.98 (s, 3H), 4.33 (t, 2H), 6.87 (s, 1H), 6.96 (d,1H), 7.19 (d, 1H), 7.38 (t, 1H), 7.43 (s, 1H), 7.55-7.61 (m, 7H), 8.54(s, 1H), 8.80 (s, 1H), 9.33 (s, 1H); LC-MS (ESI) m/z 650 (M+H)⁺.

Example 397 Preparation of1-(3-(6,7-Dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea

Example 397A Step 1:1-(4-fluoro-3-methoxyphenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)ureawas obtained following the procedure described in Example 274B forsynthesis of1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea,substituting 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline with4-fluoro-3-methoxyaniline, and phenyl3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate with1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate in Example 161(0.153 g, 62% yield). ¹H NMR (300 MHz, CDCl₃) δ 3.84 (s, 3H), 6.17 (m,1H), 6.31 (dd, 1H), 6.57 (m, 2H), 6.86 (t, 2H), 6.99 (dd, 1H), 7.10 (dd,1H), 7.42-7.51 (m, 3H); LC-MS (ESI) m/z 395 (M+H)⁺.

Example 397A Step 2: To a solution of1-(4-fluoro-3-methoxyphenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea(0.985 g, 2.5 mmol) in DCM (30 mL) at ice-water bath was dropped a 1.0 Msolution of BBr₃ in DCM (25 mL) and it was stirred for 2 hours. Thereaction mixture was quenched with saturated NaHCO₃ solution andextracted with DCM. Extracts were dried over MgSO₄ and concentrated. Thecrude product was purified on a silica gel column using a mixture ofEtOAc-hexane as eluent to give phenyl1-(4-fluoro-3-hydroxyphenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)ureaas solid (0.327 g, 34%). ¹H NMR (300 MHz, DMSO-d₆) δ 6.59 (s, 1H), 6.65(d, 1H), 6.78 (dd, 1H), 7.34 (m, 2H), 7.49 (m, 2H), 7.57 (d, 1H), 7.65(d, 1H), 8.54 (s, 1H), 8.94 (s, 1H), 10.00 (s, 1H); LC-MS (ESI) m/z 381(M+H)⁺.

Example 397B: After a mixture of1-(4-fluoro-3-hydroxyphenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea(0.22 g, 0.58 mmol) and Cs₂CO₃ (0.325 g, 1 mmol) in THF (10 mL) wasstirred at room temperature for 1 hour, to it was added4-chloro-6,7-dimethoxyquinazoline (0.13 g, 0.58 mmol). It was stirred at40° C. for 14 hours. The mixture was quenched by water and extractedwith DCM. Extracts were dried over MgSO₄ and concentrated. It waspurified on a silica gel column using a mixture of EtOAc-hexane aseluent to give1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea(0.064 g, 19% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 3.99 (s, 3H), 4.00 (s,3H), 6.87 (s, 1H), 7.24 (m, 1H), 7.36 (t, 1H), 7.42 (s, 1H), 7.59 (m,6H), 7.67 (dd, 1H), 8.56 (s, 1H), 8.83 (s, 1H), 9.32 (s, 1H); LC-MS(ESI) m/z 569 (M+H)⁺.

Example 398 Preparation of1-(3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

Example 398A Step 1: 5-Bromo-2-methoxy-pyridine (1.1 g, 5.85 mmol) in 15mL dry toluene was treated with benzophenone hydrazone (1.25 g, 6.45mmol), (2-Biphenyl)ditert-butylphosphine (55 mg, 0.18 mmol), sodiumtert-butoxide (845 mg, 8.80 mmol), and Pd₂(dba)₃ (55 mg, 0.06 mmol).Heated to 120° C. in the microwave for five minutes. Extracted usingEtOAc/H₂O (3×100 mL EtOAc, 1×100 mL H₂O, 1×100 mL brine). Dried usingNa₂SO₄ and then purified by flash chromatography (silica, 2-10%MeOH/DCM) to afford5-(2-(diphenylmethylene)hydrazinyl)-2-methoxypyridine (1.20 g, 3.96mmol, 68%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.09 (s, 1H),7.67-7.29 (m, 11H), 6.70 (d, 1H), 3.77 (s, 3H); LC-MS (ESI) m/z 304(M+H)⁺.

Example 398A Step 2:5-(2-(Diphenylmethylene)hydrazinyl)-2-methoxypyridine (1.20 g, 3.96mmol) was treated with 4,4-dimethyl-3-oxopentanenitrile (740 mg, 5.90mmol) and 6N HCl (3.3 mL, 20.0 mmol) according to the proceduredescribed for Example 303A Step 2. Purification by flash chromatography(silica, 20-100% EtOAc/Hexane) afforded3-tert-butyl-1-(6-methoxypyridin-3-yl)-1H-pyrazol-5-amine (736 mg, 2.99mmol, 76%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.31 (d, 1H), 7.83 (d, 1H), 6.89(d, 1H), 5.37 (s, 1H), 5.17 (br s, 2H), 3.89 (s, 3H), 1.20 (s, 9H);LC-MS (ESI) m/z 247 (M+H)⁺.

Example 398A Step 3:3-tert-Butyl-1-(6-methoxypyridin-3-yl)-1H-pyrazol-5-amine (736 mg, 2.98mmol) was treated with phenyl chloroformate (1.50 mL, 12.0 mmol)according to the procedure in Example 118A to afford phenyl3-tert-butyl-1-(6-methoxypyridin-3-yl)-1H-pyrazol-5-ylcarbamate (665 mg,1.82 mmol, 61%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.07 (br s, 1H), 8.31 (s,1H), 7.83 (d, 1H), 7.39 (t, 2H), 7.23 (t, 1H), 7.08 (br s, 2H), 6.98 (d,1H), 6.36 (s, 1H), 3.92 (s, 1H), 1.27 (s, 9H); LC-MS (ESI) m/z 367(M+H)⁺.

Example 398B: Phenyl3-tert-butyl-1-(6-methoxypyridin-3-yl)-1H-pyrazol-5-ylcarbamate (110 mg,0.3 mmol) was treated with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline(89 mg, 0.30 mmol) (prepared as described in Example 113A) according tothe procedure in Example 115C to afford1-(3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea(74 mg, 0.13 mmol, 44%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.14 (s, 1H), 8.55(s, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 7.82 (d, 1H), 7.55 (s, 2H),7.38-7.33 (m, 2H), 7.18 (d, 1H), 6.99-6.90 (m, 2H), 6.35 (s, 1H), 3.99(s, 3H), 3.97 (s, 3H), 3.91 (s, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 570(M+H)⁺.

Example 399 Preparation of1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-ethyl-1-phenyl-1H-pyrazol-5-yl)urea

A stirred mixture of phenyl 3-ethyl-1-phenyl-1H-pyrazol-5-ylcarbamate(prepared as described in Example 352A Step 3) (0.15 g, 0.50 mmol) and3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described inExample 115B) (0.16 g, 0.50 mmol) in DMSO (2 mL) was heated at 70° C.for 15 h. After cooling to rt, the reaction mixture was diluted withethyl acetate (50 mL) and washed with water (2×20 mL). The organic layerwas separated, dried over magnesium sulfate, and concentrated underreduced pressure to afford an oil which was recrystallized from diethylether. Further purification via preparative silica gel thin-layerchromatography (eluting with a mixture of 8% methanol in dichloromethanecontaining 0.5% ammonia) afforded1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-ethyl-1-phenyl-1H-pyrazol-5-yl)urea(90 mg, 35%) as a colorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (s,1H), 8.67 (s, 1H), 8.61 (s, 1H), 7.77 (s, 1H), 7.17-7.53 (m, 10H), 6.30(s, 1H), 3.98 (s, 6H), 2.56 (m, 2H), 1.19 (m, 3H); LC-MS (ESI) m/z 527(M+H)⁺.

Example 400 Competition Binding Assay to Determine Binding Constants(K_(d)) for Interactions Between Compounds and RAF Kinases

Competition binding assays used herein were developed, validated andperformed as described in Fabian et al., Nature Biotechnology 2005,23,329-336. Kinases were produced as fusions to T7 phage (See, Fabian etal. or WO04/015142) or alternatively, the kinases were expressed inHEK-293 cells and subsequently tagged with DNA for PCR detection (See,WO08/005,310). For the binding assays, streptavidin-coated magneticbeads were treated with biotinylated affinity ligands for 30 min at roomtemperature to generate affinity resins. The liganded beads were blockedwith excess biotin and washed with blocking buffer (SeaBlock (Pierce),1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reducenon-specific binding. Binding reactions were assembled by combiningkinase, liganded affinity beads, and test compounds in 1× binding buffer(20% SeaBlock, 0.17×PBS, 0.05% Tween 20, 6 mM DTT). Test compounds wereprepared as 100× stocks in DMSO and rapidly diluted into the aqueousenvironment. DMSO was added to control assays lacking a test compound.Primary screen interactions were performed in polypropylene 384-wellplates in a final volume of 34 μL, while K_(d) determinations wereperformed in polystyrene 96-well plates in a final volume of 135 pt. Theassay plates were incubated at room temperature with shaking for 1 hour,long enough for binding reactions to reach equilibrium, and the affinitybeads were washed extensively with wash buffer (1×PBS, 0.05% Tween 20)to remove unbound protein. The beads were then resuspended in elutionbuffer (1×PBS, 0.05% Tween 20, 2 μM non-biotinylated affinity ligand)and incubated at room temperature with shaking for 30 min. The kinaseconcentration in the eluates was measured by quantitative PCR. Eachkinase was tested individually against each compound. K_(d)s weredetermined using eleven serial threefold dilutions. A selectivity score,which is a quantitative measure of selectivity of a compound against apanel of enzymes, may be calculated for a compound by dividing thenumber of enzymes for which a compound meets a set criteria, (forexample, a binding constant of 100 nM or less), by the total number ofenzymes tested. Table 1 provides a kinase selectivity score, S35, whichwas calculated for each compound by dividing the number of kinases forwhich a compound displayed inhibition of 65% or greater compared tonegative control lacking inhibitors (DMSO only), divided by the 290distinct kinases tested excluding mutant variants. (Note, for thosecompounds tested in a larger kinase panel, as indicated by an asterisk(*) next to the S35 score, the divisor is 321 (i.e. the larger panelcontains 321 distinct kinases, excluding mutant variants.)).

Example 401 MEK Phosphorylation ELISA

A MEK1 phosphorylation ELISA (Biosource, MEK1 [pSpS218/222] kit, Catalog#KHO0321) was used to measure the inhibition of MEK1 phosphorylation inthe A375 human melanoma cell line in the presence of the compoundsprovided herein. The A375 cell line contains wild-type N-Ras but has aconstitutively active BRAF carrying the V600E mutation. A total MEKELISA was also run in parallel in order to measure the amount of bothphosphorylated and unphosphorylated MEK 1(Biosource, tMEK kit, Catalog#KH00291).

A375 cells (from American Type Culture Collection) were plated at 50,000cells per well in DMEM (Mediatech) with 10% fetal bovine serum (OmegaScientific) into a 96 well plate and incubated overnight in a 37° C.incubator with 10% CO₂. The cells were then washed with PBS and themedium replaced with 0.5% FBS for incubation overnight. A solution ofthe test compound in DMSO was added to each well at varyingconcentrations, or alternatively, a solution of positive control (aninternal compound previously determined to have an IC50 of less than 20nM in this phospho-MEK assay), or negative control (DMSO) was added tothe wells at varying concentrations. The cells were incubated withcompound or control for two hours at 37° C. The compound solution wasaspirated off and the cells washed with cold PBS. The cells were thenlysed for 30 minutes in the cold with Cell Extraction Buffer containingPhosphatase Inhibitors (catalog #FNN0011, Invitrogen) and proteaseinhibitors (catalog #11873580001, Roche Applied Science). The plate wascentrifuged for 30 minutes to pellet out the cell debris. The clearedlysates were transferred to a 96-well Nunc plate and the ELISA protocoldescribed by the manufacturer in Catalog #KH00321 or KH00291 wasfollowed. The reaction was read at 450 nM using an ELISA plate reader.The percent inhibition of MEK1 phosphorylation was determined for eachcompound at each concentration, and the concentration of the testcompound necessary for inhibiting 50% of MEK1 phosphorylation (IC₅₀) wascalculated. The results are summarized in Table 1.

Example 402 A375 Proliferation Assay

A375 cells (derived from a human melanoma cell line containing wild-typeN-Ras but which also has a constitutively active BRAF carrying the V600Emutation obtained from ATCC), were plated at 10,000 cells per well intoa 96 well TC-treated plate in M3 medium (Mediatech Cell grow) containing10% fetal bovine serum (Omega-Scientific) and incubated overnight in a37° C. incubator under 10% CO2. The following day, the medium wasreplaced with 0.5% FBS in M3 for overnight incubation. At day three, asolution of the test compound in DMSO was added to each well at varyingconcentrations, or alternatively, a solution of positive control (aninternal compound previously determined to have an IC₅₀ of less than 20nM in the phospho-MEK assay) in DMSO, or negative control (DMSO) wasadded to the wells at varying concentrations. The cells were incubatedwith compound or control for 72 hours at 37° C. under 10% CO₂. Followingincubation, Cell Titer Blue reagent (Promega) was added to each wellcontaining compounds or controls, and then incubated for 3 hours at 37°C. under 10% CO2. Proliferation was measured by fluorescence withexcitation at 560 nm and emission at 590 nm using SoftMax Pro. Thepercent inhibition of proliferation was determined for each compound ateach concentration, and the concentration of the test compound necessaryfor inhibiting cell proliferation by 50% (IC₅₀) was calculated. Theresults are summarized in Table 1.

Since modifications will be apparent to those of skill in the art, it isintended that the claimed subject matter be limited only by the scope ofthe appended claims.

1-33. (canceled)
 34. A compound having formula XVII:

or a pharmaceutically acceptable salt thereof, wherein X is O or S;R^(1a) and R^(1b) are selected as follows: i) R^(1a) and R^(1b) are eachindependently alkoxy, alkoxyalkoxy, alkylsulfonylalkoxy or a group offormula:

where K is a direct bond or alkylene, optionally substituted with ahydroxy group; A is N or CH; Y is —O, —S(O)₂, —N(R¹⁴) or —C(H)R¹⁵; p is0 or 1; R¹⁴ is hydrogen, alkyl, haloalkyl, hydroxyalkyl or S(O)_(t)R¹³;R¹⁵ is hydrogen, halo, alkyl, hydroxyalkyl or —OR¹²; t is 1 or 2; R¹² ishydrogen or alkyl; and R¹³ is alkyl; or ii) R^(1a) and R^(1b) groupstogether form an alkylenedioxy group; and R¹⁰ is hydrogen, halo, alkyl,aryl, heterocyclyl, heteroaryl, cycloalkyl or cycloalkylalkyl; wherealkyl, aryl, heterocyclyl and heteroaryl groups are optionallysubstituted with 1-3 groups selected from halo, cyano, hydroxyl andalkoxy.
 35. The compound of claim 1 having formula XIX:

or a pharmaceutically acceptable salt thereof, wherein X is O or S;R^(1a) and R^(1b) are selected as follows: i) R^(1a) and R^(1b) are eachindependently methoxy, methoxyethoxy, methylsulfonylpropyloxy, or agroup of formula:

where K is ethylene or propylene, optionally substituted with a hydroxygroup; A is N or CH; Y is —O, —S(O)₂, —N(R¹⁴) or —C(H)R¹⁵; p is 1; R¹⁴is hydrogen, methyl, hydroxyethyl, or methylsulfonyl; R¹⁵ is hydrogen,hydroxymethyl, hydroxyethyl or hydroxy; or ii) R^(1a) and R^(1b) groupstogether with the carbon atoms on which they are substituted form anethylenedioxy group; and R¹⁰ is hydrogen, halo, alkyl, aryl,heterocyclyl, heteroaryl, cycloalkyl or cycloalkylalkyl; where alkyl,aryl, heterocyclyl and heteroaryl groups are optionally substituted with1-3 groups selected from halo, cyano, hydroxyl and alkoxy.
 36. Acompound of claim 1 that is1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureaor a pharmaceutically acceptable salt thereof.
 37. A compound that is


38. A pharmaceutically acceptable salt of the compound


39. A composition comprising1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureaor a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier, excipient or diluent.
 40. A method of treating acancer associated with activated BRAF kinase comprising administering toa patient in need thereof1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureaor a pharmaceutically acceptable salt thereof.
 41. The method of claim40, wherein the cancer is melanoma.
 42. The method of claim 40, whereinthe cancer is thyroid cancer.
 43. The method of claim 40, wherein thecancer is colorectal cancer.
 44. The method of claim 40, wherein thecancer is non-small cell lung cancer.
 45. A method of inhibiting theactivity of a mutated form of BRAF kinase by administering1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureaor a pharmaceutically acceptable salt thereof.
 46. The method of claim45, wherein the mutated form is a V600 mutant.
 47. The method of claim46, wherein the V600 mutant is V600E.